This invention relates to nonsteroidal compounds that are modulators (i.e., agonists, partial agonists and antagonists) of androgen and progesterone receptors, and to methods for the making and use of such compounds.
Intracellular receptors (IRs) form a class of structurally-related genetic regulators scientists have named xe2x80x9cligand dependent transcription factorsxe2x80x9d (R. M. Evans, Science, 240:889, 1988). Steroid receptors are a recognized subset of the IRs, including androgen receptor (AR), progesterone receptor (PR), estrogen receptor (ER), glucocorticoid receptor (GR), and mineralocoticoid receptor (MR). Regulation of a gene by such factors requires both the IR itself and a corresponding ligand, which has the ability to selectively bind to the IR in a way that affects gene transcription.
The natural hormones for steroid receptors have been known for a long time, such as testosterone for AR and progesterone for PR. A synthetic compound that binds to an IR and mimics the effect of the native hormone is referred to as an xe2x80x9cagonistxe2x80x9d, while a compound that inhibits the effect of the native hormone is called an xe2x80x9cantagonistxe2x80x9d. The term xe2x80x9cmodulatorsxe2x80x9d refers to a group of compounds that have a spectrum of activities from agonist, partial agonist to antagonist.
Androgen and progesterone receptor modulators are known to play an important role in health of both men and women. For example, AR antagonists, such as cyproterone acetate, flutamide and casodex, are useful in the treatment of prostatic hyperplasia and cancer of the prostate. AR agonists, such as fluoxymesterone, are used in the treatment of hypogonadism. PR agonists, such as medroxyprogesterone acetate, are used in birth control formulations in combination with the female hormone estrogen or a synthetic estrogen analogue. Further, antagonists of PR are potentially useful for contraception and in the treatment of chronic disorders, such as certain hormone dependent cancers of the breast, ovary and uterus. Due to increased life expectancies, development of tissue selective, safer, orally active AR and PR modulators are desirable to improve quality of life.
A group of hydroquinoline derivatives was recently described as AR and PR modulators (e.g., U.S. Pat. Nos. 5,688,808, 5,688,810, 5,693,646, 5,693,647, 5,696,127, 5,696,130). This group of AR and PR modulators was developed by using cell-based high-throughput assays, termed cotransfection assays. Amino- or hydroxy-trifluoromethylquinolones or coumarins have been described as fluorescent markers in biological systems. See, e.g., U.S. Pat. No. 4,505,852 and E. R. Bissel et al., xe2x80x9cSynthesis and Chemistry of 7-Amino-4-(trifluoromethyl)coumarin and Its Amino Acid and Peptide Derivativesxe2x80x9d, J. Org. Chem., 45:2283, 1980). Analogues of quinolone, oxindole, benzooxazinone derivatives have been described as cardiotonic agents. See, e.g., U.S. Pat. Nos. 3,993,656; 4,415,572; 4,427,654; 4,710,507; 4,728,653; 4,933,336; 5,081,242.
The present invention is directed to compounds, pharmaceutical compositions, and methods for modulating processes mediated by AR and PR. More particularly, the invention relates to nonsteroidal compounds and compositions that are high affinity, high specificity agonists, partial agonists (i.e., partial activators and/or tissue-specific activators) and antagonists for AR and PR. Also provided are methods of making such compounds and pharmaceutical compositions, as well as critical intermediates used in their synthesis.
For a better understanding of the invention, its advantages, and objects obtained by its use, reference should be had to the accompanying descriptive matter, in which preferred embodiments of the invention are described.
In accordance with the present invention and as used herein, the following structure definitions are provided for nomenclature purposes. Furthermore, in an effort to maintain consistency in the naming of compounds of similar structure but differing substituents, the compounds described herein are named according to the following general guidelines.
The term xe2x80x9calkylxe2x80x9d refers to an optionally substituted straight-chain or branched-chain hydrocarbon radical having from 1 to about 10 carbon atoms, preferably from 1 to about 6 carbon atoms, and most preferably from 1 to about 4 carbon atoms. Examples of alkyl radical include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, octyl and the like.
The term xe2x80x9calkenylxe2x80x9d refers to a straight-chain or branched-chain hydrocarbon radical having one or more carbon-carbon double-bonds and having from 2 to about 10 carbon atoms, preferably from 2 to about 6 carbon atoms, and most preferably from 2 to about 4 carbon atoms. Preferred alkeny groups include allyl. Examples of alkenyl radicals include ethenyl, propenyl, 1,4-butadienyl and the like.
The term xe2x80x9callylxe2x80x9d refers to the radical H2Cxe2x95x90CHxe2x80x94CH2.
The term xe2x80x9calkynylxe2x80x9d refers to a straight-chain or branched-chain hydrocarbon radical having one or more carbon-carbon triple-bonds and having from 2 to about 10 carbon atoms. Examples of alkynyl radicals include ethynyl, propynyl, butynyl and the like.
The term xe2x80x9carylxe2x80x9d refers to optionally substituted aromatic ring systems. The term aryl includes monocyclic aromatic rings, polycyclic aromatic ring systems, and polyaromatic ring systems. The polyaromatic and polycyclic ring systems may contain from two to four, more preferably two to three, and most preferably two, rings. Preferred aryl groups include 5-or 6-membered aromatic ring systems.
The term xe2x80x9cheteroarylxe2x80x9d refers to optionally substituted aromatic ring systems having one or more heteroatoms such as, for example, oxygen, nitrogen and sulfur. The term heteroaryl may include five- or six-membered heterocyclic rings, polycyclic heteroaromatic ring systems, and polyheteroaromatic ring systems where the ring system has from two to four, more preferably two to three, and most preferably two, rings. The terms heterocyclic, polycyclic heteroaromatic, and polyheteroaromatic include ring systems containing optionally substituted heteroaromatic rings having more than one heteroatom as described above (e.g., a six membered ring with two nitrogens), including polyheterocyclic ring systems from two to four, more preferably two to three, and most preferably two, rings. The term heteroaryl includes ring systems such as, for example, pyridine, quinoline, furan, thiophene, pyrrole, imidazole and pyrazole.
The term xe2x80x9calkoxyxe2x80x9d refers to an alkyl ether radical wherein the term alkyl is defined as above. Examples of alkoxy radicals include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy and the like.
The term xe2x80x9caryloxyxe2x80x9d refers to an aryl ether radical wherein the term aryl is defined as above. Examples of aryloxy radicals include phenoxy, benzyloxy and the like.
The term xe2x80x9ccycloalkylxe2x80x9d refers to a saturated or partially saturated monocyclic, bicyclic or tricyclic alkyl radical wherein each cyclic moiety has about 3 to about 8 carbon atoms. Examples of cycloalkyl radicals include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
The term xe2x80x9ccycloalkylalkylxe2x80x9d refers to an alkyl radical as defined above which is substituted by a cycloalkyl radical having from about 3 to about 8 carbon atoms.
The term xe2x80x9caralkylxe2x80x9d refers to an alkyl radical as defined above in which one hydrogen atom is replaced by an aryl radical as defined above, such as, for example, benzyl, 2-phenylethyl and the like.
The terms alkyl, alkenyl, and alkynyl include optionally substituted straight-chain, branched-chain, cyclic, saturated and/or unsaturated structures, and combinations thereof.
The terms haloalkyl, haloalkenyl and haloalkynyl include alkyl, alkenyl and alkynyl structures, as described above, that are substituted with one or more fluorines, chlorines, bromines or iodines, or with combinations thereof.
The terms heteroalkyl, heteroalkenyl and heteroalkynyl include optionally substituted alkyl, alkenyl and alkynyl structures, as described above, in which one or more skeletal atoms are oxygen, nitrogen, sulfur, or combinations thereof.
The substituents of an xe2x80x9coptionally substitutedxe2x80x9d structure include, for example, one or more, preferably 1 to 4, more preferably 1 to 2 of the following preferred substituents: alkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy, aryloxy, cycloalkyl, cycloalkylalkyl, arylalkyl, amino, alkylamino, dialkylamino, F, Cl, Br, I, CN, NO2, NH2, NHCH3, N(CH3)2, SH, SCH3, OH, OCH3, OCF3, CH3, CF3, C(O)CH3, CO2CH3, CO2H and C(O)NH2.
Examples of compounds of the present invention are represented by those having the formula: 
wherein:
R1 and R2 each independently represent COR3, CSR3, SO2R3, NO, NR3R4, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C8 haloalkyl, C2-C8 haloalkenyl, C2-C8 haloalkynyl, C1-C8 heteroalkyl, C2-C8 heteroalkenyl, C2-C8 heteroalkynyl, (CH2)nR3, aryl, or heteroaryl and wherein the alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, and heteroaryl may be optionally substituted with F, Cl, Br, I, OR3, NR3R4, SR3, SOR3, SO2R3, C1-C4 alkyl, C1-C4 haloalkyl or C1-C4 heteroalkyl, or alternatively,
R1 and R2 may be taken together to form a three- to nine-membered alkyl, alkenyl, heteroalkyl, or heteroalkenyl ring and wherein the alkyl, alkenyl, heteroalkyl, or heteroalkenyl ring may be optionally substituted with F, Cl, Br, I, NR3R4, C1-C4 alkyl, C1-C4 haloalkyl or C1-C4 heteroalkyl, or
R1 and R2 may be taken together to form one of: 
Preferably, R1 and R2 may be taken together to form: 
Most preferably, R1 and R2 may be taken together to form: 
Most preferably, R1 and R2 may be taken together to form: 
RA represents hydrogen, ORC, O2CRC, (CH2)nORC, NHRC, NHCORC, F, Cl, Br, I, CN, SCN, SCH3;
RB represents hydrogen, F, Cl, Br, I, CHF2, CF3, C1-C6 alkyl, aryl, heteroaryl, wherein the alkyl, aryl and heteroaryl may be optionally substituted with F, Cl, Br, I, CN, NO2, OH, OCH3, CF3, C1-C6 alkyl;
RC represents hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C8 haloalkyl, C1-C8 heteroalkyl, (CH2)nRD;
RD represents aryl or heteroary, optionally substituted with F, Cl, Br, I, CN, NO2, OH, OCH3, CF3, C1-C6 alkyl;
R3 and R4 each independently represent hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C8 haloalkyl, C1-C8 heteroalkyl, heteroaryl, or aryl and wherein the alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, heteroaryl, and aryl may be optionally substituted with halogen, C1-C4 alkyl, C1-C4 haloalkyl or C1-C4 heteroalkyl;
R5 represents hydrogen, F, Cl, Br, I, OR3, SR3, SOR3, SO2R3, NR3R4, C1-C4 alkyl, C1-C4 haloalkyl or C1-C4 heteroalkyl;
R6 represents F, Cl, Br, I, CH3, CF3, CHF2, CFH2, CN, CF2Cl, CF2OR3, OR3, SR3, SOR3, SO2R3, NR3R4, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C2-C4 haloalkenyl, C2-C4 haloalkynyl, C1-C4 heteroalkyl, C2-C4 heteroalkenyl, or C2-C4 heteroalkynyl and wherein the alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, and heteroaryl may be optionally substituted with halogen, C1-C4 alkyl, C1-C4 haloalkyl or C1-C4 heteroalkyl;
R7 and R8 each independently represent hydrogen, F, Cl, Br, I, CN, OR3, NR3R4, NR3CR3R4CONR3R4, Cn(R3)2nOR3, SR3, SOR3, SO2R3, NR3COR4, C1-C8 alkyl, C1-C8 haloalkyl, or C1-C8 heteroalkyl;
R9 represents hydrogen, F, Br, Cl, I, OR3, NR3R4, SR3, SOR3, SO2R3, C1-C4 alkyl, C1-C4 haloalkyl or C1-C4 heteroalkyl;
R10 represents one of: 
R11 represents hydrogen, F, Br, Cl, I, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, NO2, CN, CF3, OR3, NR3R4, SR3, SOR3, or SO2R3;
R12 is F, Br, Cl, I, CN, OR3, SR3, SOR3, SO2R3, NR3R4, C1-C4 alkyl, C1-C4 haloalkyl or C1-C4 heteroalkyl;
R13 represents hydrogen, F, Cl, Br, I, CN, OR1, NHR1, COR3, CO2R3, SR1, SOR3, SO2R3, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C8 haloalkyl, C2-C8 haloalkenyl, C2-C8 haloalkynyl, C1-C8 heteroalkyl, C2-C8 heteroalkenyl, C2-C8 heteroalkynyl, (CH2)nR3, or heteroaryl and wherein the alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, (CH2)nR3, and heteroaryl may be optionally substituted with F, Cl, Br, I, CN, NO2, NR1R3, SR, SOR3, SO2R3, C1-C4 alkyl, C1-C4 haloalkyl or C1-C4 heteroalkyl;
R14 represents F, Br, Cl, I, CF3, CHF2, CH2F, CF2Cl, or CF2OR3;
R15 represents hydrogen, F, Br, Cl, I, CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 heteroalkyl, OR16, NR16R4, SR16, CH2R16, COR3, CO2R3, CONR3R4, SOR3, or SO2R3;
R16 represents hydrogen, C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 heteroalkyl, aryl, heteroaryl, COR17, CO2R17, or CONR17R17;
R17 represents hydrogen, C1-C4 alkyl, C1-C4 haloalkyl or C1-C4 heteroalkyl;
R18 and R19 each independently represent hydrogen, C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 heteroalkyl, or alternatively, R18 and R19 may be taken together to form a three- to seven-membered ring;
R20 represents an aryl or heteroaryl wherein the aryl or heteroaryl may be optionally substituted with F, Cl, Br, CN, OR1, SR1, SOR3, SO2R3, NO2, NR1R3, C1-C4 alkyl, C1-C4 haloalkyl or C1-C4 heteroalkyl;
R21 represents CR3R4CONR3R4, Cn(R3)2nOR3, SOR3, SO2R3, C2-C8 alkyl, C2-C8 haloalkyl, and C2-C8 heteroalkyl;
R22 and R23 each independently represent hydrogen, C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 heteroalkyl, or alternatively R22 and R23 may be taken together to form a three- to seven-membered ring;
R24 represents hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 heteroalkyl, or OR3;
R25 through R30 each independently represent hydrogen, F, Cl, Br, I, OR3, NR3R4, SR3, SOR3, SO2R3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C2-C6 alkynyl or C2-C6 alkenyl, and wherein the alkyl, haloalkyl, heteroalkyl, alkynyl, and alkenyl may be optionally substituted with F, Cl, Br, I, OR3, NR3R4, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 heteroalkyl, aryl or heteroaryl and wherein the aryl and heteroaryl may be optionally substituted with F, Cl, Br, I, CN, NO2, OH, OCH3, CF3 or C1-C6 alkyl;
Any two of R25 through R30 when taken together can form a three to seven-membered alkyl or alkenyl or heteroalkyl ring; or any four of R25 through R30 when taken together can form a fused aromatic ring;
Q represents O or S;
U represents V, OCR22R23, SCR22R23, NR3CR22R23, CR3R4CR22R23;
V represents O, S, NR3, CR22R23, CR3R4O, or CR3R4S, but, V is not S when R1 and R2 are both methyl;
W represents O, S, NR3, CR25R26;
X represents O, S or NR16;
Y represents O, S, NR3, NOR3 or CR3R4;
Z represents O, S, NR3, Cxe2x95x90O, or CR3R4, or optionally Z may represent two hydrogens;
n is 1, 2, 3 or 4; and
m is 1 to 5.
Preferred R1 and R2 groups include COR3, CSR3, SO2R3, C1-C8 alkyl, C2-C8 alkenyl, C1-C8 haloalkyl, C2-C8 haloalkenyl, C2-C8 heteroalkyl, C2-C8 heteroalkenyl, (CH2)nR3A, aryl, and heteroaryl, wherein the aryl, or heteroaryl may be optionally substituted with F, Cl, Br, OR3, NR3R4, CN, NO2, SR3, COMe, COCF3, C1-C4 alkyl, C1-C4 haloalkyl. Also preferred, R1 and R2 groups may be taken together to form one of: 
More preferred R1 and R2 groups include COR, C1-C8 alkyl, C2-C8 alkenyl, C1-C8 haloalkyl, C2-C8 haloalkenyl, C1-C8 heteroalkyl, CH2R3A, aryl and heteroaryl. The aryl or heteroaryl may be optionally substituted with F, Cl, Br, OH, OMe, SH, SMe, CN, NO2, CF3, Me, COMe, or R1 and R2 groups may be taken together to form: 
Most preferably, R1 and R2 groups include C1-C8 alkyl, C2-C8 alkenyl, C1-C8 haloalkyl, C1-C8 heteroalkyl, and CH2R3A, or, R1 and R2 groups may be taken together to form: 
Preferred R3 and R4 groups include hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C1-C8 haloalkyl, and C1-C8 heteroalkyl. More preferred R3 and R4 groups include hydrogen, C1-C6 alkyl and C1-C8 haloalkyl. Most preferably, R3 and R4 each independently is selected from group of hydrogen, C1-C6 alkyl, and C1-C6 haloalkyl.
Preferred R3A groups include aryl and heteroaryl, wherein the aryl and heteroaryl may be optionally substituted with halogen, CN, OMe, SMe, C1-C4 alkyl, or C1-C4 haloalkyl. More preferred R3A groups include heteroaryl and aryl, wherein the heteroaryl and aryl may be optionally substituted with F, Cl, Br, CN, OMe, C1-C4 alkyl, or C1-C4 haloalkyl. Most preferably, R3A groups include heteroaryl and aryl, wherein the heteroaryl and aryl may be optionally substituted with F, Cl, Br, CN, CF3, OMe, or C1-C4 alkyl.
Preferred R5 groups include hydrogen, F, Cl, Br, OH, OMe, C1-C4 alkyl, and C1-C4 haloalkyl. More preferred R5 groups include hydrogen, F, Cl, OH, OMe, C1-C4 alkyl, and CF3. Most preferred R5 groups include hydrogen, F, Cl, OH, and OMe.
Preferred R6 groups include F, Cl, Br, CH3, CF3, CHF2, CFH2, CN, CF2Cl, CF2OR3, OR3, SR3, NR3R4, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C2-C4 haloalkenyl, C1-C4 heteroalkyl, and C2-C4 heteroalkenyl. More preferred R6 groups include F, Cl, Br, CF3, CHF2, CFH2, CN, CF2Cl, CF2OMe, and C1-C4 alkyl. Most preferred R6 groups include F, Cl, C1-C4 alkyl, CF3, CHF2, CFH2, CF2Cl, CF2OMe, and OMe.
Preferred R7 groups include hydrogen, F, Cl, Br, OR3, NR3R4, SR3, C1-C8 alkyl, C1-C8 haloalkyl, or C1-C8 heteroalkyl. More preferred R7 groups include hydrogen, F, Cl, Me, OMe, and CF3. Most preferred R7 groups include hydrogen, F, Cl, Me, and OMe.
Preferred R8 groups include hydrogen, F, Cl, Br, OR3, NR3R4, SR3, C1-C8 alkyl, C1-C8 haloalkyl, and C1-C8 heteroalkyl. More preferred R8 groups include hydrogen, F, Cl, Br, OR3, NR3R4, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 heteroalkyl. Most preferred R8 groups include hydrogen, F, Cl, Br, OR3, NR3R4, C1-C6 alkyl, C1-C6 haloalkyl.
Preferred R9 groups include hydrogen, F, Br, Cl, OR3, NR3R4, SR3, C1-C4 alkyl, and C1-C4 haloalkyl. More preferred R9 groups include hydrogen, F, Br, OH, Me, OMe, and CF3. Most preferred R9 groups include hydrogen, F, Cl, OH, Me, OMe, and CF3.
Preferred R10 groups include: 
More preferred R10 groups include: 
Preferred R11 groups include F, Br, Cl, I, C1-C6 alkyl, CC1-C6 haloalkyl, NO2, CN, CF3, OH, OMe, NR3R4, and SR3. More preferred R11 groups include F, Br, Cl, C1-C6 alkyl, NO2, CN, CF3, OH, OMe.
Preferred R12 groups include F, Br, Cl, and C1-C4 haloalkyl. More preferred R12 groups include F, Br, Cl, CF3, CF2H and CFH2.
Preferred R13 groups include hydrogen, F, Cl, Br, I, CN, OR3, NR3R4, SR3, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C8 haloalkyl, C2-C8 haloalkenyl, C2-C8 haloalkynyl, C1-C8 heteroalkyl, and (CH2)nR3A. More preferred R13 groups include hydrogen, F, Cl, Br, OR3, SR3, C1-C8 alkyl, C2-C8 alkenyl, C1-C8 haloalkyl. Most preferred R13 groups include hydrogen, F, Cl, Br, C1-C4 alkyl, C2-C4 alkenyl, or C1-C8 haloalkyl.
Preferred R13A groups include NHR1 or heteroaryl, wherein the heteroaryl may be optionally substituted with F, Cl, Br, CN, NMe2, NO2, CF3, Me or OMe. More preferred R13A is NHR1.
Preferred R14 groups include F, Br, Cl, CF3, CHF2, CH2F, CF2Cl, and CF2OMe. More preferred R14 groups include F, Cl, CF3, CHF2, CH2F, and CF2Cl. Most preferred R14 groups include Cl, CF3, CHF2, CH2F, and CF2Cl.
Preferred R15 groups include F, Br, Cl, CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 heteroalkyl, OR16, NR16R4, and SR16. More preferred R15 groups include F, Cl, CN, OR16, and SR16. Most preferred R15 groups include Cl, OR16, NR16R4 and SR16.
Preferred R16 groups include hydrogen, C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 heteroalkyl, COR17, CO2R17, and CONR17R17. More preferred R16 groups include hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, COR17, CO2R17, and CONR17R17. Most preferred R16 groups include hydrogen, C1-C6 alkyl, COR17; CO2R17, and CONR17R17.
Preferred R17 groups include C1-C4 alkyl, C1-C4 haloalkyl and C1-C4 heteroalkyl.
Preferred R18 and R19 groups include C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl and R18 and R19 may be taken together to form a four- to seven-membered ring. More preferred R18 and R19 groups include C1-C6 alkyl, and C1-C6 haloalkyl and R18 and R19 may be taken together to form a five- to six-membered ring. Most preferred R18 and R19 groups include C1-C4 alkyl, C1-C4 haloalkyl and R18 and R19 may be taken together to form a five- to six-membered ring.
Preferred R20 groups include aryl and heteroaryl. The aryl or heteroaryl may be optionally substituted with F, Cl, Br, CN, NO2, CF3 and C1-C4 alkyl.
Preferred R21 groups include C2-C8 alkyl, C2-C8 haloalkyl, and C2-C8 heteroalkyl. More preferred R21 groups include C2-C8 alkyl, and C2-C8 haloalkyl.
Preferred R22 and R23 groups include hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 heteroalkyl and R22 and R23 groups may be taken together to form a three- to seven-membered ring. More preferred R22 and R23 groups include hydrogen, C1-C6 alkyl, C1-C6 haloalkyl and R22 and R23 groups taken together to form a four- to six-membered ring.
Preferred R24 groups include hydrogen and OR3. More preferred R24 groups include hydrogen and OH.
Preferred R25, R26, R27, R28, R29 and R30 groups include hydrogen, F, Cl, Br, OR3, NR3R4, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, and C2-C6 alkenyl, wherein the alkyl, haloalkyl, heteroalkyl, alkynyl, or alkenyl may be optionally substituted with F, Cl, Br, OR3, NR3R4, aryl or heteroaryl and the aryl and heteroaryl may be optionally substituted with F, Cl, Br, CN, NO2, OH, OCH3, CF3 or C1-C6 alkyl. Also preferred is any two of R25, R26, R27, R28, R29 and R30 groups taken together to form a three- to seven-membered alkyl or alkenyl or heteroalkyl ring. Also preferred is any four of R25, R26, R27, R28, R29 and R30 groups taken together to form a fused aromatic ring. More preferred R25 through R30 groups include hydrogen, F, Cl, OH, OMe, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl and C2-C6 alkenyl. Also more preferred is any two of R25, R26, R27, R28, R29 and R30 groups taken together to form a four to six-membered alkyl or alkenyl ring. Also more preferred is any four of R25, R26, R27, R28, R29 and R30 groups taken together to form a fused aromatic ring. Most preferred R25 through R30 groups include hydrogen, F, Cl, OH, OMe, C1-C4 alkyl, and C1-C4 haloalkyl.
Preferably Q is O.
Preferred U groups include V, OCR22R23, NR3CR22R23, CR3R4CR22R23.
Preferred V groups include CR22R23, CR3R4O, and CR3R4S.
Preferred W groups include O, NR3, and CR3R4. More preferred W groups include O, and CR3R4. Most preferably, W is O.
Preferred X groups include S and NR16. More preferred X groups include O and NR16. Most preferably, X is NR16.
Preferred Y groups include O, S, NR3, and NOR3. More preferred Y groups include O, S, and NOR3. Most preferably, Y is O or S.
Preferred Z groups include O, S, NR3, CR25R26 and two hydrogens. More preferred Z groups include O, CR25R26 and two hydrogens. Most preferably, Z groups include O, CR3R4 and two hydrogens.
Preferably, n is 1 or 2.
Preferably, m is 1 to 4. More preferably, m is 1 to 3.
In a preferred embodiment of the invention, R1 and R2 are each independently selected from the group of COR3, CSR3, SO2R3, NO, NR3R4, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C8 haloalkyl, C2-C8 haloalkenyl, C2-C8 haloalkynyl, C1-C8 heteroalkyl, C2-C8 heteroalkenyl, C2-C8 heteroalkynyl, (CH2)nR3A, aryl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, and heteroaryl are optionally substituted with F, Cl, Br, I, OR3, NR3R4, CN, NO2, SR3, SOR3, SO2R3, C1-C4 alkyl, C1-C4 haloalkyl or C1-C4 heteroalkyl. R3 and R4 are each independently hydrogen or optionally substituted C1-C6 alkyl. R3A is optionally substituted alkyl or heteroaryl. R5 is selected from the group of hydrogen, halogen and optionally substituted C1-C6 alkyl. R7 and R8 are each independently hydrogen or halogen; and R9 is hydrogen or halogen. R11 is selected from the group of halogen, CN, NO2 and optionally substituted C1-C6 haloalkyl. R12 is halogen or optionally substituted haloalkyl. R13 is selected from the group of hydrogen C1-C6 alkyl and C1-C6 heteroalkyl, wherein said C1-C6 alkyl and C1-C6 heteroalkyl are optionally substituted. R15is halogen or OR16. R18 and R19 are each independently optionally substituted C1-C6 alkyl; or R18 and R19 taken together form a five- to six-membered ring. R22 and R23 are each independently hydrogen or optionally substituted C1-C6 alkyl; or R22 and R23 together form a three- to seven-membered ring. R25 through R30 are each independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl, wherein said C1-C6 alkyl and C1-C6 haloalkyl are optionally substituted; Y is selected from the group of O, S, and NR3; and m is 1 to 3.
In another preferred embodiment of the invention R1 and R2 taken together form a three- to nine-membered alkyl, alkenyl, heteroalkyl, or heteroalkenyl ring, wherein the alkyl, alkenyl, heteroalkyl, or heteroalkenyl ring are optionally substituted with F, Cl, Br, I, OR3, NR3R4, C1-C4 alkyl, C1-C4 haloalkyl or C1-C4 heteroalkyl. R3 and R4 are each independently hydrogen or optionally substituted C1-C6 alkyl. R3A is optionally substituted alkyl or heteroaryl. R5 is selected from the group of hydrogen, halogen and optionally substituted C1-C6 alkyl. R7 and R8 are each independently hydrogen or halogen. R9 is hydrogen or halogen. R11 is selected form the group of halogen, CN, NO2 and optionally substituted C1-C6 haloalkyl. R12 is halogen or optionally substituted haloalkyl. R13 is selected from the group of hydrogen, C1-C6 alkyl and C1-C6 heteroalkyl, wherein said C1-C6 alkyl and C1-C6 heteroalkyl are optionally substituted. R15 is halogen or OR16, R18 and R19 are each independently optionally substituted C1-C6 alkyl; or R18 and R19 taken together form a five- to six-membered ring. R22 and R23 are each independently hydrogen or optionally substituted C1-C6 alkyl; or R22 and R23 together form a three- to seven-membered ring. R25 through R30 are each independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl, wherein said C1-C6 alkyl and C1-C6 haloalkyl are optionally substituted. Y is selected from the group of O, S, and NR3; and m is 1 to 3.
In still another preferred embodiment of the invention, R1 and R2 taken together form one of: 
R3 and R4 are each independently hydrogen or optionally substituted C1-C6 alkyl. R3A is optionally substituted alkyl or heteroaryl. R5 is selected from the group of hydrogen, halogen and optionally substituted C1-C6 alkyl. R7 and R8 are each independently hydrogen or halogen. R9 is hydrogen or halogen. R11 is selected form the group of halogen, CN, NO2 and optionally substituted C1-C6 haloalkyl. R12 is halogen or optionally substituted haloalkyl. R13 is selected from the group of hydrogen C1-C6 alkyl and C1-C6 heteroalkyl, wherein said C1-C6 alkyl and C1-C6 heteroalkyl are optionally substituted. R15 is halogen or OR16, R18 and R19 are each independently optionally substituted C1-C6 alkyl; or R18 and R19 taken together form a five- to six-membered ring. R22 and R23 are each independently hydrogen or optionally substituted C1-C6 alkyl; or R22 and R23 together form a three- to seven-membered ring. R25 through R30 are each independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl, wherein said C1-C6 alkyl and C1-C6 haloalkyl are optionally substituted; Y is selected from the group of O, S, and NR3; and m is 1 to 3.
The present invention further provides methods of modulating processes mediated by AR or PR or combinations thereof comprising administering to a patient an effective amount of a pharmaceutical composition of the present invention comprising one or more compounds represented by those having the following formulas as well as pharmaceutical compositions of the above compounds: 
wherein:
R1 and R2 each independently represent COR3, CSR3, SO2R3, NO, NR3R4, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C8 haloalkyl, C2-C8 haloalkenyl, C2-C8 haloalkynyl, C1-C8 heteroalkyl, C2-C8 heteroalkenyl, C2-C8 heteroalkynyl, (CH2)nR3, aryl, or heteroaryl and wherein the alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, heteroalkynyl, aryl, and heteroaryl may be optionally substituted with F, Cl, Br, I, OR3, NR3R4, SR3, SOR3, SO2R3 C1-C4 alkyl, C1-C4 haloalkyl or C1-C4 heteroalkyl, or alternatively,
R1 and R2 may be taken together to form a three- to nine-membered alkyl, alkenyl, heteroalkyl, or heteroalkenyl ring and wherein the alkyl, alkenyl, heteroalkyl, and heteroalkenyl ring may be optionally substituted with F, Cl, Br, I, OR3, NR3R4, C1-C4 alkyl, C1-C4 haloalkyl or C1-C4 heteroalkyl, or
R1 and R2 may be taken together to form one of: 
R3 and R4 each independently represent hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C1-C8 alkynyl, C1-C8 haloalkyl, C1-C8 heteroalkyl, heteroaryl, or aryl and wherein the alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, heteroaryl, and aryl may be optionally substituted with halogen, C1-C4 alkyl, C1-C4 haloalkyl or C1-C4 heteroalkyl;
R5 represents hydrogen, F, Cl, Br, I, OR3, SR3, SOR3, SO2R3, NR3R4, C1-C4 alkyl, C1-C4 haloalkyl or C1-C4 heteroalkyl;
R7 and R8 each independently represent hydrogen, F, Cl, Br, I, CN, OR3, NR3R4, NR3CR3R4CONR3R4, Cn(R3)2nOR3, SR3, SOR3, SO2R3, NR3COR4, C1-C8 alkyl, C1-C8 haloalkyl, or C1-C8 heteroalkyl;
R9 represents hydrogen, F, Br, Cl, I, OR3, NR3R4, SR3, a C1-C4 alkyl, C1-C4 haloalkyl or C1-C4 heteroalkyl;
R11 represents hydrogen, F, Br, Cl, I, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, NO2, CN, CF3, OR3,NR3R4, SR3, SOR3 or SO2R3;
R15 represents hydrogen, F, Br, Cl, I, CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 heteroalkyl, OR16, NR16R4, SR16, CH2R16, COR3, CO2R3, CONR3R4, SOR3, or SO2R3;
R16 represents hydrogen, C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 heteroalkyl, aryl, heteroaryl, COR17, CO2R17, or CONR17R17;
R17 represents hydrogen, C1-C4 alkyl, C1-C4 haloalkyl or C1-C4 heteroalkyl;
R18 and R19 each independently represent hydrogen, C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 heteroalkyl, or alternatively, R18 and R19 may be taken together to form a three- to seven-membered ring;
R22 and R23 each independently represent hydrogen, C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 heteroalkyl, or alternatively, R22 and R23 may be taken together to form a three- to seven-membered ring;
R24 represents hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 heteroalkyl, or OR3;
R25 through R30 each independently represent hydrogen, F, Cl, Br, I, OR3, NR3R4, SR3, SOR3, SO2R3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C2-C6 alkynyl or C2-C6 alkenyl, and wherein the alkyl, haloalkyl, heteroalkyl, alkynyl, and alkenyl may be optionally substituted with F, Cl, Br, I, OR3, NR3R4, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 heteroalkyl, aryl or heteroaryl and wherein the aryl and heteroaryl may be optionally substituted with F, Cl, Br, I, CN, NO2, OH, OCH3, CF3 or C1-C6 alkyl;
Any two Rs of R25 through R30 when taken together can form a three to seven-membered alkyl or alkenyl or heteroalkyl ring; or any four Rs of R25 through R30 when taken together can form a fused aromatic ring;
R31 represents hydrogen, F, Cl, Br, I, CN, OR1, NHR1, COR3, CO2R3, SR1, SOR3, SO2R3, C1-C8 alkyl, C2-C8 alkenyl, C1-C8 haloalkyl, C2-C8 haloalkenyl, C1-C8 heteroalkyl, C2-C8 heteroalkenyl, C2-C8 alkynyl, C2-C8 haloalkynyl, C2-C8 heteroalkynyl, (CH2)nR3 or heteroaryl and wherein the alkyl, alkenyl, haloalkyl, haloalkenyl, heteroalkyl, heteroalkenyl, allyl, alkynyl, haloallyl, haloalkynyl, heteroalkynyl, (CH2)nR3, and heteroaryl may be optionally substituted with F, Cl, Br, I, CN, OR1, NO2, NR1R3, SR1, SOR3, SO2R3, C1-C4 alkyl, C1-C4 haloalkyl, or C1-C4 heteroalkyl or optionally,
R31 represents one of: 
R42 represents hydrogen, F, Cl, Br, I, CH3, CF3, CHF2, CFH2, CN, CF2Cl, CF2OR3, OR3, SR3, SOR3, SO2R3, NR3R4, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C2-C4 haloalkenyl, C2-C4 haloalkynyl, C1-C4 heteroalkyl, C2-C4 heteroalkenyl, or C2-C4 heteroalkynyl, and wherein the alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, and heteroaryl may be optionally substituted with halogen, C1-C4 alkyl, C1-C4 haloalkyl or C1-C4 heteroalkyl;
M represents O, S, NR16;
U represents O, S, NR3, CR22R23, CR3R4O, or CR3R4S;
W represents O, S, NR3, CR22R23;
X represents O, S or NR16, but when R31 is an aryl or heteroaryl, X is not NR16;
Y represents O, S, NR16, NOR16 or CR116R17;
Z represents O, S, NR3, Cxe2x95x90O, or CR3R4, or optionally Z may represent two hydrogens;
n is 1, 2 or 3; and
m is 1 to 5.
In a preferred aspect, the present invention provides a pharmaceutical composition comprising an effective amount of an AR or PR modulating compound of formulas I through XIII shown above wherein R1 through R42, M, Q, U, V, W, X, Y and Z all have the same definitions as given above.
In a further preferred aspect, the present invention comprises a method of modulating processes mediated by ARs or PRs or combinations comprising administering to a patient an effective amount of a compound of the formulae I through XIII shown above wherein R1 through R42, M, Q, U, V, W, X, Y and Z all have the same definitions as given above.
Any of the compounds of the present invention can be synthesized as pharmaceutically acceptable salts for incorporation into various pharmaceutical compositions. As used herein, pharmaceutically acceptable salts include, but are not limited to, hydrochloric, hydrobromic, hydroiodic, hydrofluoric, sulfuric, citric, maleic, acetic, lactic, nicotinic, succinic, oxalic, phosphoric, malonic, salicylic, phenylacetic, stearic, pyridine, ammonium, piperazine, diethylamine, nicotinamide, formic, urea, sodium, potassium, calcium, magnesium, zinc, lithium, cinnamic, methylamino, methanesulfonic, picric, tartaric, triethylamino, dimethylamino, and tris(hydroxymethyl)aminomethane. Additional pharmaceutically acceptable salts are known to those skilled in the art.
AR agonist, partial agonist and antagonist compounds (including compounds with tissue-selective AR modulator activity) of the present invention are useful in the treatment of hypogonadism (agonist), male hormone replacement therapy (agonist), wasting diseases (agonist), cancer cachexia (agonist), male contraception, hirsutism (antagonist), stimulation of hematopoiesis (agonist), acne (antagonist), male-pattern baldness (antagonist), prostatic hyperplasia (antagonist), various hormone-dependent cancers, including, without limitation, prostate (antagonist),and breast cancer and as anabolic agents (agonist). It is understood by those of skill in the art that a partial agonist may be used where agonist activity is desired, or where antagonist activity is desired, depending upon the AR modulator profile of the particular partial agonist.
PR agonist, partial agonist and antagonist compounds of the present invention are useful in female hormone replacement therapy and as modulators of fertility (e.g., as contraceptives, contragestational agents or abortifacients), either alone or in junction with ER modulators. The PR modulators are also useful in the treatment of dysfunctional uterine bleeding, dysmenorrhea, endometriosis, leiomyomas (uterine fibroids), hot flashes, mood disorders, meningiomas as well as in various hormone-dependent cancers, including, without limitation, cancers of ovary, breast, endometrium and prostate.
It is understood by those skilled in the art that although the compounds of the present invention are typically employed as selective agonists, partial agonists or antagonists, there may be instances where a compound with a mixed steroid receptor profile is preferred.
Furthermore, it is understood by those skilled in the art that the compounds of the present invention, including pharmaceutical compositions and formulations containing these compounds, can be used in a wide variety of combination therapies to treat the conditions and diseases described above. Thus, the compounds of the present invention can be used in combination with other hormones and other therapies, including, without limitation, chemotherapeutic agents such as cytostatic and cytotoxic agents, immunological modifiers such as interferons, interleukins, growth hormones and other cytokines, hormone therapies, surgery and radiation therapy.
Representative AR modulator compounds (i.e., agonists and antagonists) according to the present invention include:
6-Amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 200);
6-Propylamino-4-trifluoromethyl-2(1H)-quinolinone (Compound 204);
6-Isopropylamino-4-trifluoromethyl-2(1H)-quinolinone (Compound 205);
6-Isobutylamino-4-trifluoromethyl-2(1H)-quinolinone (Compound 206);
6-(2,2-Dimethylpropyl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 207);
6-Cyclopentylamino-4-trifluoromethyl-2(1H)-quinolinone (Compound 208);
6-(2,2,2-Trifluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 209);
6-(2,2,3,3,3-Pentafluoropropyl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 210);
6-(2,2-Difluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 211);
6-(2-Chloro-2,2-difluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 212);
6-Acetylamino-4-trifluoromethyl-2(1H)-quinolinone (Compound 213);
6-Trifluoroacetylamino-4-trifluoromethyl-2(1H)-quinolinone (Compound 214);
6-Benzoylamino-4-trifluoromethyl-2(1H)-quinolinone (Compound 215);
6-Dimethylacetylamino-4-trifluoromethyl-2(1H)-quinolinone (Compound 216);
6-Dimethylamino-4-trifluoromethyl-2(1H)-quinolinone (Compound 217);
6-Diethylamino-4-trifluoromethyl-2(1H)-quinolinone (Compound 218);
6-Dipropylamino-4-trifluoromethyl-2(1H)-quinolinone (Compound 219);
6-Dibutylamino-4-trifluoromethyl-2(1H)-quinolinone (Compound 220);
6-Diisobutylamino-4-trifluoromethyl-2(1H)-quinolinone (Compound 221);
6-(bis-Cyclopropylmethyl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 222);
6-(bis-2,2,2-Trifluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 223);
6-(bis-2,2,3,3,3-Pentafluoropropyl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 224);
6-(bis-2-Chloro-2,2-difluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 225);
6-(bis-2-Bromoethyl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 226);
6-(N-2,2,2-Trichloroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 227);
6-(bis-N-2,2,2-Trichloroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 228);
6-(N-2,2,2-Chlorodifluoroethyl-N-2,2,2-Trichloroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 229);
6-(bis-N-2,2-Difluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 230);
6-(N-2,2-Dichloroethyl-N-2,2,2-trichloroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 231);
6-(bis-N-2,2-Dichloroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 232);
6-(N-2,2-Dichloroethyl-N-2,2-difluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 233);
6-(N-2,2-Dichloroethyl-N-2,2,2-chlorodifluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 234);
6-(N-Isopropyl-N-methyl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 235);
6-(N-Methyl-N-cyclopentyl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 236);
6-(N-Methyl-N-isobutyl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 237);
6-(N-Ethyl-N-propyl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 238);
6-(N-Ethyl-N-isopropyl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 239);
6-(N-Ethyl-N-1-methylpropyl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 240);
6-(N-Ethyl-N-isobutyl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 241);
6-(N-Ethyl-N-2,2-dimethylpropyl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 242);
6-(N-Ethyl-N-cyclopentyl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 243);
6-(N-Ethyl-N-1-acetylethyl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 244);
(xc2x1)-6-(N-Ethyl-N-1-methyl-2-hydroxypropyl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 245);
6-(N-Ethyl-N-2,2,2-trifluoroethyl)amino-4-trifluoromethyl-2(H11)-quinolinone (Compound 246);
6-(N-Ethyl-N-3-furylmethyl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 247);
(xc2x1)-6-(N-Ethyl-N-2,2-dimethoxyisopropyl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 248);
6-(N-Isopropyl-N-propyl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 249);
6-(N-2-Hydroxyethyl-N-propyl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 250);
(xc2x1)-6-(N-Propyl-N-1-methylbutyl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 251);
(xc2x1)-6-(N-Propyl-N-1,2-dimethylpropyl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 252);
6-(N-Propyl-N-isobutyl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 253);
6-(N-Propyl-N-cyclopropylmethyl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 254);
(xc2x1)-6-(N-Propyl-N-1-methylpropyl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 255);
6-(N-2-Hydroxyethyl-N-isopropyl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 256);
6-(N-Isopropyl-N-cyclopropylmethyl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 257);
6-(N-Methyl-N-2,2,2-trifluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 258);
6-(N-2,2,2-trifluoroethyl-N-isobutyl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 259);
6-(N-2,2,2-trifluoroethyl-N-isopropyl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 260);
6-(N-2,2,2-Trifluoroethyl-N-cyclopropylmethyl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 261);
(xc2x1)-6-(N-2,2,2-Trifluoroethyl-N-1-methylpropyl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 262);
(xc2x1)-6-(N-2,2,2-Trifluoroethyl-N-2-chloroisopropyl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 263);
(+)-6-(N-2,2,2-Trifluoroethyl-N-2-chloroisopropyl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 264);
(xe2x88x92)-6-(N-2,2,2-Trifluoroethyl-N-2-chloroisopropyl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 265);
6-(N-2,2,2-Trifluoroethyl-N-3-furfuryl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 266);
6-(N-2,2,2-Trifluoroethyl-N-3-thiophenemethyl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 267);
6-(N-2,2,2-Trifluoroethyl-N-3,3-dimethylbutyl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 268);
6-(N-2,2,2-Trifluoroethyl-N-2-thiophenemethyl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 269);
6-(N-2,2,2-Trifluoroethyl-N-2-furfuryl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 270);
6-(N-Butyl-N-2,2,2-trifluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 271);
6-(bis-N,N-Benzyl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 272);
6-(N-2,2,2-Trifluoroethyl-N-cyclobutyl)amino-4-trifluoromethyl-2(1H)-quinolinone 12 (Compound 273);
6-(N-2,2,2-Trifluoroethyl-N-2,2-dichloroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 274);
6-(N-2,2,2-Trifluoroethyl-N-2-chloroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 275);
6-(N-Benzyl-N-2,2,2-trifluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 276);
6-(N-4-Fluorobenzyl-N-2,2,2-trifluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 277);
6-(N-Propyl-N-2,2,2-trifluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 278);
6-(N-2,2,3,3,3-Pentafluoropropyl-N-2,2,2-trifluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 279);
6-Diallylamino-4-trifluoromethyl-2(1H)-quinolinone (Compound 280);
6-(N-Isobutyl-N-allyl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 281);
6-(N-Isopropyl-N-allyl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 282);
6-(N-Allyl-N-2,2,2-trifluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 283);
6-Allylamino-4-trifluoromethyl-2(1H)-quinolinone (Compound 284);
6-(N-Allyl-N-cyclopropylmethyl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 285);
6-(N-Allyl-N-2,2,2-trifluoroacetyl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 286);
6-(N-2,2,2-Trifluoroethyl-N-2,2,2-trifluoroacetyl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 287);
6-(N-Allyl-N-propyl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 288);
(xc2x1)-6-(N-2-Hydroxyisopropyl-N-2,2,2-trifluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 289);
(xc2x1)-6-(N-Isobutyl-N-2,2,2-trifluoroisopropyl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 290);
6-(N-2,2-Difluoroethyl-N-2,2,2-trifluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 291);
6-(N-2,2-Dimethylpropyl-N-2,2,2-trifluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 292);
6-(N-2,2-Difluoro-2-chloroethyl-N-2,2,2-trifluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 293);
6-(N-2,2-Difluoro-2-chloroethyl-N-2,2-difluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 294);
6-(N-2,2,2-Trifluoroethyl-N-methylsufonyl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 295);
1-Methyl-6-(N-propyl-N-isobutyl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 296);
1-Methyl-6-(bis-2,2,2-trifluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 297);
1-Ethyl-6-(bis-2,2,2-trifluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 298);
6-(N-2,2,2-Trifluoroethyl)amino-4-trifluoromethyl-2(1H)-thioquinolinone (Compound 299);
6-(bis-N,N-2,2,2-Trifluoroethyl)amino-4-trifluoromethyl-2(1H)-thioquinolinone (Compound 300);
(xc2x1)-6-(N-2,2,2-Trifluoroethyl-N-2,2,2-trifluoroisopropyl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 301);
(+)-6-(N-2,2,2-Trifluoroethyl-N-2,2,2-trifluoroisopropyl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 302);
(xe2x88x92)-6-(N-2,2,2-Trifluoroethyl-N-2,2,2-trifluoroisopropyl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 303);
6-Methoxythiocarbonylmercapto-4-trifluoromethyl-2(1H)-quinolinone (Compound 304);
6-Mercapto-4-trifluoromethyl-2(1H)-quinolinone (Compound 305);
6-(1,1-Dimethyl-2-propynyl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 306);
6-tert-Butylamino-4-trifluoromethyl-2(1H)-quinolinone (Compound 307);
6-Bromo-4-trifluoromethyl-2(1H)-quinolinone (Compound 308);
6-Bromo-4-trifluoromethyl-2-isopropyloxyquinoline (Compound 309);
6-tert-Butylamino-2-isopropyloxy-4-trifluoromethylquinolines (Compound 310);
6-(1-Piperdinyl)-4-trifluoromethyl-2(1H)-quinolinone (Compound 311);
6-(1-Pyrrolidinyl)-4-trifluoromethyl-2(1H)-quinolinone (Compound 312);
6-(1-Morpholino)-4-trifluoromethyl-2(1H)-quinolinone (Compound 313);
(xc2x1)-6-(2-Methyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone (Compound 314);
(+)-6-(2-Methyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone (Compound 315);
(xe2x88x92)-6-(2-Methyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone (Compound 316);
6-(N-phenylamino)-4-trifluoromethyl-2(1H)-quinolinone (Compound 317);
6-(N-phenyl-N-ethylamino)-4-trifluoromethyl-2(1H)-quinolinone (Compound 319);
6-(N-phenyl-N-ethylamino)-4-trifluoromethyl-2-isopropyloxyquinoline (Compound 320);
6-(N-phenyl-N-2,2,2-trifluoroethylamino)-4-trifluoromethyl-2(1H)-quinolinone (Compound 321);
(xc2x1)-6-(3-Methyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone (Compound 322);
6-(4-Methyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone (Compound 323);
6-(cis-3,5-Dimethyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone (Compound 324);
6-(2,6-cis-Dimethyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone (Compound 325);
6-(2,6-trans-Dimethyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone (Compound 326);
(xc2x1)-6-(2-Methyl-1-pyrrolidino)-4-trifluoromethyl-2(1H)-quinolinone (Compound 327);
6-(2,5-cis-Dimethyl-1-pyrrolidino)-4-trifluoromethyl-2(1H)-quinolinone (Compound 328);
(xc2x1)-6-(2,5-trans-Dimethyl-1-pyrrolidino)-4-trifluoromethyl-2(1H)-quinolinone (Compound 329);
6-(1-Azepano)-4-trifluoromethyl-2(1H)-quinolinone (Compound 330);
(xc2x1)-6-(2-Hydroxymethyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone (Compound 331);
6-(2,5-cis-Dimethyl-1-pyrrolino)-4-trifluoromethyl-2(11)-quinolinone (Compound 332);
(xc2x1)-6-(2-Propyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone (Compound 333);
(xc2x1)-6-(2-Methoxymethyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone (Compound 334);
(xc2x1)-6-(2-Ethyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone (Compound 335);
6-(1-Cycloheptylamino)-4-trifluoromethyl-2(1H)-quinolinone (Compound 336);
(xc2x1)-6-(2-Ethoxycarbonyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone (Compound 337);
(xc2x1)-6-(2-Isopropyl-1-pyrrolidino)-4-trifluoromethyl-2(1H)-quinolinone (Compound 338);
(xc2x1)-6-(2-Hydroxycarbonyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone (Compound 339);
6-(3,5-cis-Dimethyl-1-piperazino)-4-trifluoromethyl-2(1H)-quinolinone (Compound 340);
(xc2x1)-6-(2-Benzyl-1-pyrrolidino)-4-trifluoromethyl-2(1H)-quinolinone (Compound 341);
(xc2x1)-6-(5-Methyl-2-oxo-1-pyrrolidino)-4-trifluoromethyl-2(1H)-quinolinone (Compound 342);
(xc2x1)-6-(2-(2-Hydroxyethyl)-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone (Compound 343);
(xc2x1)-6-(3-Hydroxy-1-pyrrolidino)-4-trifluoromethyl-2(1H)-quinolinone-(Compound 344);
(xc2x1)-6-(3-Acetyloxy-1-pyrrolidino)-4-trifluoromethyl-2(1H)-quinolinone (Compound 345);
(xc2x1)-6-(3-Hydroxy-1-pyrrolidino)-4-trifluoromethyl-2(1H)-quinolinone (Compound 346);
6-(1-Indolino)-4-trifluoromethyl-2(1H)-quinolinone (Compound 347);
6-(1-Tetrahydroquinolino)-4-trifluoromethyl-2(1H)-quinolinone (Compound 348);
6-(2-Tetrahydroisoquinolino)-4-trifluoromethyl-2(1H)-quinolinone (Compound 349);
(xc2x1)-6-(1,3,3-Trimethyl-6-azabicyclo[3.2.1]octanyl-6-)-4-trifluoromethyl-2(1H)-quinolinone (Compound 350);
(xc2x1)-6-(2-Trifluoromethyl-5-cis-methyl-1-oxazolidino)-4-trifluoromethyl-2(1H)-quinolinone (Compound 351);
(xc2x1)-6-(2-Trifluoromethyl-5-trans-methyl-1-oxazolidino)-4-trifluoromethyl-2(1H)-quinolinone (Compound 352);
6-N-(1-Hydroxyisopropyl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 353);
(xc2x1)-6-(2-Trifluoromethyl-5-cis-ethyl-1-oxazolidino)-4-trifluoromethyl-2(1H)-quinolinone 270 (Compound 354);
(xc2x1)-6-(2-Trifluoromethyl-5-trans-ethyl-1-oxazolidino)-4-trifluoromethyl-2(1H)-quinolinone (Compound 355);
(xc2x1)-6-(5-Methyl-1-oxazolidino)-4-trifluoromethyl-2(1H)-quinolinone (Compound 356);
6-(2,5-Dimethyl-1-pyrrolyl)-4-trifluoromethyl-2(1H)-quinolinone (Compound 357);
6-(N-2,2,2-Trifluoroethyl-N-3,3,3-trifluoropropyl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 358);
6-(N-3,3,3-Trifluoropropyl)amino-4-trifluoromethyl-2-isopropyloxyquinoline (Compound 360);
6-bis-N,N-Thiomethoxymethylamino-4-trifluoromethyl-2(1H)-quinolinone (Compound 361);
6-bis-N,N-Thiomethoxymethylamino-4-trifluoromethyl-2-thiomethoxymethyloxyquinoline (Compound 362);
(xc2x1)-6-(2,5-trans-Diethyl-1-pyrrolidino)-4-trifluoromethyl-2(1H)-quinolinone (Compound 363);
6-(2,5-cis-Diethyl-1-pyrrolidino)-4-trifluoromethyl-2(1H)-quinolinone (Compound 364);
(xc2x1)-6-(2,5-trans-Dipropyl-1-pyrrolidino)-4-trifluoromethyl-2(1H)-quinolinone (Compound 365);
6-(2,5-cis-Dipropyl-1-pyrrolidino)-4-trifluoromethyl-2(1H)-quinolinone (Compound 366);
6-(2,5-Dipropyl-1-pyrrolo)-4-trifluoromethyl-2(1H)-quinolinone (Compound 367);
6-(2,5-cis-Dibutyl-1-pyrrolidino)-4-trifluoromethyl-2(1H)-quinolinone (Compound 368);
(xc2x1)-6-(2,5-trans-Dibutyl-1-pyrrolidino)-4-trifluoromethyl-2(1H)-quinolinone (Compound 369);
6-(2,6-cis-Diethyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone (Compound 370);
(xc2x1)-6-(2,6-trans-Diethyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone (Compound 371);
6-(2,6-cis-Dimethyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone (Compound 372);
(xc2x1)-6-(2,6-trans-Dimethyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone (Compound 373);
6-(N-Propyl-N-2,2,2-trifluoroethyl)amino-4-methyl-2(1H)-quinolinone (Compound 374);
6-Amino-4-methyl-2(1H)-quinolinone (Compound 375);
6-(bis-2,2,2 Trifluoroethyl)amino-4-methyl-2(1H)-quinolinone (Compound 377);
6-(2,5-Dimethyl-1-pyrrolyl)-4-methyl-2(1H)-quinolinone (Compound 378);
(xc2x1)-6-(2,5-trans-dimethyl-1-pyrrolidino)-4-methyl-2(1H)-quinolinone (Compound 379);
6-(2,5-cis-dimethyl-1-pyrrolidino)-4-methyl-2(1H)-quinolinone (Compound 380);
6-(N-Isobutyl-N-2,2,2-trifluoroethyl)amino-4-methyl-2(1H)-quinolinone (Compound 381);
6-(N-2,2,2-Chlorodifluoroethyl)amino-4-methyl-2(1H)-quinolinone (Compound 382);
6-(bis-N,N-2,2,2-Chlorodifluoroethyl)amino-4-methyl-2(1H)-quinolinone (Compound 383);
6-(N-2,2,2-Chlorodifluoroethyl-N-2,2,2-trifluoroethyl)amino-4-methyl-2(1H)-quinolinone (Compound 384);
6-N-Ethylamino-4-methyl-2(1H)-quinolinone (Compound 385);
6-(N-Ethyl-N-2,2 2-trifluoroethyl)amino-4-methyl-2(1H)-quinolinone (Compound 386);
6-N,N-Diethylamino-4-methyl-2(1H)-quinolinone (Compound 387);
6-(bis-2,2,2-trifluoroethyl)amino-4-ethyl-2(1H)-quinolinone (Compound 388);
6-Amino-4-ethyl-2(1H)-quinolinone (Compound 389);
6-(bis-2,2,2-trifluoroethyl)amino-4-isopropyl-2(1H)-quinolinone (Compound 391);
6-Amino-4-isopropyl-2(1H)-quinolinone (Compound 392);
7-Fluoro-6-(bis-trifluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 393);
7-Fluoro-4-trifluoromethyl-2(1H)-quinolinone (Compound 394);
5-Fluoro-4-trifluoromethyl-2(1H)-quinolinone (Compound 395);
6-Amino-7-fluoro-4-trifluoromethyl-2(1H)-quinolinone (Compound 396);
8-Fluoro-6-(bis-2,2,2-trifluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 397);
8-Fluoro-4-trifluoromethyl-2(1H)-quinolinone (Compound 316); 6-Amino-8-fluoro-4-trifluoromethyl-2(1H)-quinolinone (Compound 399);
8-Fluoro-6-(N-2,2,2-trifluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 400);
8-Fluoro-6-(N-2,2,2-trifluoroethyl-N-isopropyl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 401);
6-Amino-3-fluoro-4-trifluoromethyl-2(1H)-quinolinone (Compound 402);
3-Fluoro-6-(2,2,2-trifluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 403);
3-Fluoro-6-(bis-2,2,2-trifluorofluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 404);
6-(bis-Isobutylamino)-4-methyl-2(1H)-quinolinone (Compound 405);
3-Fluoro-6-(N-methyl-N-2,2,2-trifluorofluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 406);
7-Bromo-6-isopropylamino-4-trifluoromethyl-2(1H)-quinolinone (Compound 407);
6-Amino-7-bromo-4-trifluoromethyl-2(1H)-quinolinone (Compound 408);
6-(bis-N,N-2,2,2-Trifluoroethyl)amino-4-hydroxy-2(1H)-quinolinone (Compound 409);
6-amino-4-hydroxy-2(1H)-quinolinone (Compound 410);
6-(bis-N,N-2,2,2-Trifluoroethyl)amino-4-methoxy-2(1H)-quinolinone (Compound 411);
6-amino-4-methoxy-2(1H)-quinolinone (Compound 412);
6-(bis-N,N-2,2,2-Trifluoroethyl)amino-4-difluoromethyl-2(1H)-quinolinone (Compound 413);
6-amino-4-difluoromethyl-2(1H)-quinolinone (Compound 414);
6-(bis-N,N-2,2,2-Trifluoroethyl)amino-2(1H)-quinolinone (Compound 415);
6-amino-2(1H)-quinolinone (Compound 416);
4-Chloro-6-(bis-N,N-2,2,2-trifluoroethyl)amino-2(1H)-quinolinone (Compound 417);
6-amino-4-chloro-2(1H)-quinolinone (Compound 418);
7-Methoxy-4-trifluoromethyl-2(1H)-quinolinone (Compound 419);
5,7-Dimethoxy-4-trifluoromethyl-2(1H)-quinolinone (Compound 420);
(R)-6-(2-Hydroxymethyl-1-pyrrolidino)-4-trifluoromethyl-2(1H)-quinolinone (Compound 421);
(R)-6-(2-Methoxycarbonyl-1-pyrrolidino)-4-trifluoromethyl-2-isopropyloxyquinoline (Compound 422);
(R)-6-(2-Methoxymethyl-1-pyrrolidino)-4-trifluoromethyl-2(1H)-quinolinone (Compound 423);
(xc2x1)-6-(2-Chloromethyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone (Compound 424);
(xc2x1)-6-(2-Cyanothiomethyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone (Compound 425);
(xc2x1)-6-(2-Thiomethoxymethyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone (Compound 426);
(xc2x1)-6-(2-Cyanomethyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone (Compound 427);
(xc2x1)-6-(2-Bromomethyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone (Compound 428);
(xc2x1)-6-(2-Iodomethyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone (Compound 429);
(+)R-6-(2-Iodomethyl-1-pyrrolidino)-4-trifluoromethyl-2(1H)-quinolinone (Compound 430);
(xc2x1)-6-(2-Fluoromethyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone (Compound 431);
(+)S-6-(2-Chloromethyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone (Compound 432);
(xe2x88x92)R-6-(2-Chloromethyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone (Compound 433);
(+)R-6-(2-Chloromethyl-1-pyrrolidino)-4-trifluoromethyl-2(1H)-quinolinone (Compound 434);
(xe2x88x92)S-6-(2-Chloromethyl-1-pyrrolidino)-4-trifluoromethyl-2(1H)-quinolinone (Compound 435);
R-6-(2-Difluoromethyl-1-pyrrolidino)-4-trifluoromethyl-2(1H)-quinolinone (Compound 436);
(xc2x1)-6-(2l-(1l-Hydroxy-2,2,2-trifluoroethyl)-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone (Compound 437);
(xc2x1)-6-(2l-(1u-Hydroxy-2,2,2-trifluoroethyl)-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone (Compound 438);
(xc2x1)-6-(2-Formyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone (Compound 439);
(xc2x1)-6-(2-Difluoromethyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone (Compound 440);
(xc2x1)-6-(2-Aminomethyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone (Compound 441);
(R)-6-(2-Vinyl-1-pyrrolidino)-4-trifluoromethyl-2(1H)-quinolinone (Compound 442);
(R)-6-(2-Formyl-1-pyrrolidino)-4-trifluoromethyl-2(1H)-quinolinone (Compound 443);
(xc2x1)-6-(2-Vinyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone (Compound 444);
(xc2x1)-6-(2-Benzyloxyethyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone (Compound 445);
(xc2x1)-6-(2-(2,2-Difluoroethyl)-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone (Compound 446);
(xc2x1)-6-(2-Trifluoroacetamidomethyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone (Compound 447);
(xc2x1)-6-(2-(2-Ethoxyethyl)-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone (Compound 448);
(xc2x1)-6-(2-(4-Trifluoromethyl)benzyloxyethyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone (Compound 449);
(+)-6-(2R-(1R-Hydroxy-2,2,2-trifluoroethyl)-1-pyrrolidino)-4-trifluoromethyl-2(1H)-quinolinone (Compound 450);
(xe2x88x92)6-(2R-(1S-Hydroxy-2,2,2-trifluoroethyl)-1-pyrrolidino)-4-trifluoromethyl-2(1H)-quinolinone (Compound 451);
6-(2S-(1R-Hydroxy-2,2,2-trifluoroethyl)-1-pyrrolidino)-4-trifluoromethyl-2(1H)-quinolinone (Compound 452);
6-(2S-(1S-Hydroxy-2,2,2-trifluoroethyl)-1-pyrrolidino)-4-trifluoromethyl-2(1H)-quinolinone (Compound 453);
(xc2x1)-6-(2l-(1l-Hydroxyethyl)-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone (Compound 454);
(xc2x1)-6-(2l-(1u-Hydroxyethyl)-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone (Compound 455);
(xe2x88x92)-6-(2S-(1S-Hydroxy-2,2,2-trifluoroethyl)-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone (Compound 456);
(+)-6-(2R-(1R-Hydroxy-2,2,2-trifluoroethyl)-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone (Compound 457);
(+)-6-(2R-(1S-Hydroxy-2,2,2-trifluoroethyl)-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone (Compound 458);
(xe2x88x92)-6-(2S-(1R-Hydroxy-2,2,2-trifluoroethyl)-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone (Compound 459);
(xc2x1)-6-(2l-(1l-Acetyloxyethyl)-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone (Compound 460);
(xc2x1)-6-(2l-(1u-Acetyloxyethyl)-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone (Compound 461);
(xc2x1)-6-(2l-(1u-Methoxy-2,2,2-trifluoroethyl)-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone (Compound 462);
(xc2x1)-6-(2l-(1l-Methoxy-2,2,2-trifluoroethyl)-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone (Compound 463);
7-Methoxy-6-(N-methyl-N-2,2,2-trifluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 464);
4-Amino-2-methoxy-N-2,2,2-trifluoroethylaniline (Compound 466);
7-Methoxy-6-(N-2,2,2-trifluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 467);
7-Methoxy-6-(N-ethyl-N-2,2,2-trifluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 468);
7-Hydroxy-6-(2,2,2-trifluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 469);
6-(N-Cyclopropylmethyl-N-2,2,2-trifluoroethyl)amino-7-methoxy-4-trifluoromethyl-2(1H)-quinolinone (Compound 470);
6-(N-Cyclopropylmethyl-N-2,2,2-trifluoroethyl)amino-7-hydroxy-4-trifluoromethyl-2(1H)-quinolinone (Compound 471);
6-(N-Isobutyl-N-2,2,2-trifluoroethyl)amino-7-methoxy-4-trifluoromethyl-2(1H)-quinolinone (Compound 472);
6-(N-Isobutyl-N-2,2,2-trifluoroethyl)amino-7-hydroxy-4-trifluoromethyl-2(1H)-quinolinone (Compound 473);
6-(bis-2,2,2-Trifluoroethyl)amino-4-trifluoromethylcoumarin (Compound 474);
6-Amino-4-trifluoromethylcoumarin (Compound 475);
(xc2x1)-3,4-Dihydro-6-(bis-2,2,2-trifluoroethyl)amino-4-trifluoromethylcoumarin (Compound 476);
6-(2,2,2-trifluoroethyl)amino-4-trifluoromethylcoumarin (Compound 477);
6-(N-Isopropyl-N-2,2,2-trifluoroethyl)amino-4-trifluoromethylcoumarin (Compound 478);
6-N-Isobutylamino-4-trifluoromethylcoumarin (Compound 479);
6-N,N-Diethylamino-4-trifluoromethylcoumarin (Compound 480);
6-N,N-Dipropylamino-4-trifluoromethylcoumarin (Compound 481);
6-N-Propylamino-4-trifluoromethylcoumarin (Compound 482);
6-(N-Isobutyl-N-propylamino)-4-trifluoromethylcoumarin (Compound 483);
6-(N-2,2,2-Trifluoroethyl-N-propylamino)-4-trifluoromethylcoumarin (Compound 484);
1,4-Dihydro-4,4-dimethyl-6-methylamino-1,3-benzo[d]oxazin-2-one (Compound 485);
6-Amino-1,4-dihydro-4,4-dimethyl-1,3-benzo[d]oxazin-2-one (Compound 487);
1,4-Dihydro-4,4-dimethyl-6-dimethylamino-1,3-benzo[d]oxazin-2-one (Compound 488);
1,4-Dihydro-4,4-dimethyl-6-dipropylamino-1,3-benzo[d]oxazin-2-one (Compound 489);
1,4-Dihydro-4,4-dimethyl-6-(bis-N,N-2,2,2-trifluoroethyl)amino-1,3-benzo[d]oxazin-2-one (Compound 490);
1,4-Dihydro-4,4-dimethyl-6-(N-2,2,2-trifluoroethyl)amino-1,3-benzo[d]oxazin-2-one (Compound 491);
(xc2x1)-1,4-Dihydro-4-methyl-6-diallylamino-1,3-benzo[d]oxazin-2-one (Compound 492);
(xc2x1)-6-Amino-1,4-dihydro-4-methyl-1,3-benzo[d]oxazin-2-one (Compound 494);
6-Amino-3,4-dihydro-4,4-dimethyl-2(1H)-quinolinone (Compound 495);
6-Diallylamino-3,4-dihydro-4,4-dimethyl-2(1H)-quinolinone (Compound 497);
3,4-Dihydro-4,4-dimethyl-6-dipropylamino-2(1H)-quinolinone (Compound 498);
3,4-Dihydro-4,4-dimethyl-6-propylamino-2(1H)-quinolinone (Compound 499);
3,4-Dihydro-4,4-dimethyl-6-(N-2,2,2-trifluoroethyl)amino-2(1H)-quinolinone (Compound 500);
3,4-Dihydro-4,4-dimethyl-6-(bis-N,N-2,2,2-trifluoroethyl)amino-2(1H)-quinolinone (Compound 501);
3,4-Dihydro-6-(N-2,2,2-trifluoroethyl)amino-2(1H)-quinolinone (Compound 502);
6-Amino-3,4-dihydro-2(1H)-quinolinone (Compound 503);
3,4-Dihydro-6-(bis-N,N-2,2,2-trifluoroethyl)amino-2(1H)-quinolinone (Compound 505);
5-(bis-N,N-2,2,2-Trifluoroethyl)amino-3,3-spirocyclohexyl-2-indolone (Compound 506);
5-Amino-3-spirocyclohexyloxindole (Compound 507);
7-(bis-N,N-2,2,2-Trifluoroethyl)amino-1,4-benzoxazin-3(4H)-one (Compound 508);
7-amino-1,4-benzoxazin-3(4H)-one (Compound 509);
6-(bis-N,N-2,2,2-Trifluoroethyl)amino-2,4-dichloroquinoline (Compound 510);
6-amino-1,4-dichloro-2(1H)-quinolinone (Compound 511);
7-Amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 512);
7-Propylamino-4-trifluoromethyl-2(1H)-quinolinone (Compound 513);
7-Isopropylamino-4-trifluoromethyl-2(1H)-quinolinone (Compound 514);
7-(2,2-Dimethylpropyl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 515);
7-(2-Methylpropyl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 516);
7-Methylamino-4-trifluoromethyl-2(1H)-quinolinone (Compound 517);
7-Dimethylamino-4-trifluoromethyl-2(1H)-quinolinone (Compound 518);
7-Benzylamino-4-trifluoromethyl-2(1H)-quinolinone (Compound 519);
7-(2,2,3,3,3-Pentafluoropropyl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 520);
7-Butylamino-4-trifluoromethyl-2(1H)-quinolinone (Compound 521);
7-Ethylamino-4-trifluoromethyl-2(1H)-quinolinone (Compound 522);
7-(-2,2,2-Trifluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 523);
7-Cyclohexylamino-4-trifluoromethyl-2(1H)-quinolinone (Compound 524);
7-Cyclopentylamino-4-trifluoromethyl-2(1H)-quinolinone (Compound 525);
7-Cyclobutylamino-4-trifluoromethyl-2(1H)-quinolinone (Compound 526);
7-(2-Hydroxy-2-methylpropionyl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 527);
7-(Trifluoroacetamido)-4-trifluoromethyl-2(1H)-quinolinone (Compound 528); 1-Methyl-7-methylamino-4-trifluoromethyl-2(1H)-quinolinone (Compound 529);
1-Methyl-7-dimethylamino-4-trifluoromethyl-2(1H)-quinolinone (Compound 530);
1-Methyl-7-(N-methyl-N-isopropylamino)-4-trifluoromethyl-2(1H)-quinolinone (Compound 531);
1-Methyl-7-(2,2,2-trifluoromethyl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 532);
3-Fluoro-7-(2,2,2-trifluoromethyl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 533);
3-Fluoro-7-amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 534);
3-Fluoro-7-isopropylamino-4-trifluoromethyl-2(1H)-quinolinone (Compound 535);
3-Fluoro-7-cyclopentylamino-4-trifluoromethyl-2(1H)-quinolinone (Compound 536);
3-Fluoro-7-cyclohexylamino-4-trifluoromethyl-2(1H)-quinolinone (Compound 537);
3-Fluoro-7-cyclobutylamino-4-trifluoromethyl-2(1H)-quinolinone (Compound 538);
3-Fluoro-7-propylamino-4-trifluoromethyl-2(1H)-quinolinone (Compound 539);
3-Fluoro-1-methyl-7-(N-methyl-N-isopropyl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 540);
3-Fluoro-1-methyl-7-propylamino-4-trifluoromethyl-2(1H)-quinolinone (Compound 541);
6-Fluoro-7-amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 542);
6-Fluoro-7-propylamino-4-trifluoromethyl-2(1H)-quinolinone (Compound 543);
6-Fluoro-7-isobutylamino-4-trifluoromethyl-2(1H)-quinolinone (Compound 544);
6-Fluoro-1-methyl-7-propylamino-4-trifluoromethyl-2(1H)-quinolinone (Compound 545);
6-Fluoro-1-methyl-7-(N-methyl-N-propylamino)-4-trifluoromethyl-2(1H)-quinolinone (Compound 546);
7-Amino-6-methyl-4-trifluoromethyl-2(1H)-quinolinone (Compound 547);
7-Isobutylamino-6-methyl-4-trifluoromethyl-2(1H)-quinolinone (Compound 548);
7-Propylamino-6-methyl-4-trifluoromethyl-2(1H)-quinolinone (Compound 549);
7-(1,1-Dimethyl-3-oxobutyl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 550);
7-(1,1,3-Trimethyl-3-hydroxybutyl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 551);
7-(1,1,3-Trimethyl-3-butenylamino)-4-trifluoromethyl-2(1H)-quinolinone (Compound 552);
7-(1-Phenylaminocarbonylisopropyl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 553);
7-(2-Hydroxy-1,1-dimethylethyl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 556);
7-(N-1-Formylisopropyl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 558);
7-(1,1-Dimethylallyl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 559);
7-(1,1-Dimethylpropyl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 560);
7-(1-Methyl-1-acetylenylpropyl)amino]-4-(trifluoromethyl)-2(1H)-quinolinone (Compound 561);
7-(1-Ethyl-1-methylpropyl)amino-4-(trifluoromethyl)-2(1H)-quinolinone (Compound 562);
8-Methyl-7-(3-methyl-2-butenyl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 563);
8-Methyl-7-(3-methylbutyl)amino-4-(trifluoromethyl)-2(1H)-quinolinone (Compound 566);
8-Methyl-7-propylamino-4-(trifluoromethyl)-2(1H)-quinolinone (Compound 567);
8-Methyl-7-isobutylamino-4-(trifluoromethyl)-2(1H)-quinolinone (Compound 569);
7-Amino-6-(2,2,2-trifluoroethoxy)-4-trifluoromethyl-2(1H)-quinolinone (Compound 571);
7-Isobutylmino-6-(2,2,2-trifluoroethoxy)-4-trifluoromethyl-2(1H)-quinolinone (Compound 574);
7-(2-Picolylamino)-6-(2,2,2-trifluoroethoxy)-4-trifluoromethyl-2(1H)-quinolinone (Compound 575);
7-Amino-6-methyl-4-trifluoromethyl-2(1H)-quinolinone (Compound 576);
7-Amino-6-ethyl-4-trifluoromethyl-2(1H)-quinolinone (Compound 577);
7-Amino-6-propyl-4-trifluoromethyl-2(1H)-quinolinone (Compound 580);
7-Amino-6-sec-butyl4-trifluoromethyl-2(1H)-quinolinone (Compound 581);
7-Amino-6-cyclohexyl-4-trifluoromethyl-2(1H)-quinolinone (Compound 582);
6-Ethyl-7-(2,2,2-trifluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 585);
6-Ethyl-7-methylamino-4-trifluoromethyl-2(1H)-quinolinone (Compound 586);
6-Ethyl-7-dimethylamino-4-trifluoromethyl-2(1H)-quinolinone (Compound 587);
6-Isobutyl-7-methylamino-4-trifluoromethyl-2(1H)-quinolinone (Compound 588);
7-(1-Morpholino)-4-trifluoromethyl-2(1H)-quinolinone (Compound 589);
5-Amino-7-chloro-4-trifluoromethyl-2(1H)-quinolinone (Compound 592);
5-Propylamino-7-chloro-4-trifluoromethyl-2(1H)-quinolinone (Compound 594);
7-Chloro-5-hydroxy-4-trifluoromethyl-2(1H)-quinolinone (Compound 595);
5-Amino-6-bromo-3,4-dihydro-4-hydroxy-4-trifluoromethyl-2(1H)-quinolinone (Compound 596);
6-Bromo-5-chloro-4-trifluoromethyl-2(1H)-quinolinone (Compound 598);
6-(bis-N,N-2,2,2-trifluoroethyl)amino-5-methoxy-4-trifluoromethyl-2(1H)-quinolinone (Compound 600);
6-amino-5-methoxy-4-trifluoromethyl-2(1H)-quinolinone (Compound 601);
6-(N-2,2,2-Trifluoroethyl)amino-5-propyloxy-4-trifluoromethyl-2(1H)-quinolinone (Compound 602);
6-amino-5-propyloxy-4-trifluoromethyl-2(1H)-quinolinone (Compound 603);
6-(bis-N,N-2,2,2-Trifluoroethyl)amino-5-propyloxy-4-trifluoromethyl-2(1H)-quinolinone (Compound 604);
6-(N-2,2,2-Trifluoroethyl)amino-5-ethoxy-4-trifluoromethyl-2(1H)-quinolinone (Compound 605);
6-amino-5-ethoxy-4-trifluoromethyl-2(1H)-quinolinone (Compound 606);
6-(bis-N,N-2,2,2-Trifluoroethyl)amino-5-ethoxy-4-trifluoromethyl-2(1H)-quinolinone (Compound 607);
6-(N-2,2,2-Trifluoroethyl)amino-5-(3,3,3-trifluoropropyloxy)-4-trifluoromethyl-2(1H)-quinolinone (Compound 608);
6-amino-5-(3,3,3-trifluoropropyloxy)-4-trifluoromethyl-2(1H)-quinolinone (Compound 609);
6-(N-2,2,2-Trifluoroethyl)amino-5-chloro-4-trifluoromethyl-2(1H)-quinolinone (Compound 610);
6-amino-5-chloro-4-trifluoromethyl-2(1H)-quinolinone (Compound 611);
6-(bis-N,N-2,2,2-Trifluoroethyl)amino-5-chloro-4-trifluoromethyl-2(1H)-quinolinone (Compound 612);
6-Fluoro-4-trifluoromethyl-2(1H)-quinolinone (Compound 613);
6-Chloro-4-trifluoromethyl-2(1H)-quinolinone (Compound 614);
6-Isopropyl-4-trifluoromethyl-2(1H)-quinolinone (Compound 615);
6-Cyclohexyl-4-trifluoromethyl-2(1H)-quinolinone (Compound 616);
6-(1-trans-Propenyl)-4-trifluoromethyl-2(1H)-quinolinone (Compound 617);
6-Cyclohexyl-3-fluoro-4-trifluoromethyl-2(1H)-quinolinone (Compound 618);
7-Fluoro-6-methyl-4-trifluoromethyl-2(1H)-quinolinone (Compound 619);
5,7-Difluoro-4-trifluoromethyl-2(1H)-quinolinone (Compound 620);
6-Methoxy-4-trifluoromethyl-2(1H)-quinolinone (Compound 621);
6-Hydroxy-4-trifluoromethyl-2(1H)-quinolinone (Compound 622);
6-Benzyloxy-4-trifluoromethyl-2(1H)-quinolinone (Compound 623);
6-(3-Pentyloxy)-4-trifluoromethyl-2(1H)-quinolinone (Compound 624);
6-(1-Hydroxy-3,3,5,5-tetramethyl)cyclohexyl-4-trifluoromethyl-2(1H)-quinolinone (Compound 625);
6-(3,3,5,5-Tetramethyl)cyclohexenyl-4-trifluoromethyl-2(1H)-quinolinone (Compound 626);
6-(5,5-Dimethycyclopentenyl)-4-trifluoromethyl-2(1H)-quinolinone (Compound 627);
6-(2,2-Dimethycyclopentyl)-4-trifluoromethyl-2(1H)-quinolinone (Compound 628);
6-(1-Hydroxycyclohexyl)-4-trifluoromethyl-2(1H)-quinolinone (Compound 629);
6-Cyclohexenyl-4-trifluoromethyl-2(1H)-quinolinone (Compound 630);
6-Cyclohexyl-4-trifluoromethyl-2(1H)-thioquinolinone (Compound 631);
6-Cyclopentenyl-4-trifluoromethyl-2(1H)-quinolinone (Compound 632);
6-Cycloheptenyl-4-trifluoromethyl-2(1H)-quinolinone (Compound 633);
6-Bromo-3-fluoro-4-trifluoromethyl-2(1H)-quinolinone (Compound 634);
6-Cyclohexenyl-3-fluoro-4-trifluoromethyl-2(1H)-quinolinone (Compound 635);
6-Cyclohexyl-7-methoxy-4-trifluoromethyl-2(1H)-quinolinone (Compound 636);
6-Bromo-7-methoxy-4-trifluoromethyl-2(1H)-quinolinone (Compound 637);
6-Cyclopentyl-3-fluoro-4-trifluoromethyl-2(1H)-quinolinone (Compound 638);
(Z)-6-(1-Propyl-1-)butenyl-4-trifluoromethyl-2(1H)-quinolinone (Compound 639);
(E)-6-(1-Propyl-1-)butenyl-4-trifluoromethyl-2(1H)-quinolinone (Compound 640);
6-(1-Propyl)butyl-4-trifluoromethyl-2(1H)-quinolinone (Compound 641);
(E)-6-(1-Methyl-1-)butenyl-4-trifluoromethyl-2(1H)-quinolinone (Compound 642);
(Z)-6-(1-Methyl-1-)butenyl-4-trifluoromethyl-2(1H)-quinolinone (Compound 643);
(xc2x1)-6-(1-Methyl)butyl-4-trifluoromethyl-2(1H)-quinolinone (Compound 644);
(E)-6-(1-Ethyl-1-)propenyl-4-trifluoromethyl-2(1H)-quinolinone (Compound 645);
(Z)-6-(1-Ethyl-1-)propenyl-4-trifluoromethyl-2(1H)-quinolinone (Compound 646);
6-(1-Ethyl)propyl-4-trifluoromethyl-2(1H)-quinolinone (Compound 647);
6-(1-Isopropyl-2-methyl-1-)propenyl-4-trifluoromethyl-2(1H)-quinolinone (Compound 648);
6-(1-Isopropyl-2-methyl)propyl-4-trifluoromethyl-2(1H)-quinolinone (Compound 649);
(Z)-6-(1-Isobutyl-3-methyl-1-)butenyl-4-trifluoromethyl-2(1H)-quinolinone (Compound 650);
(E)-6-(1-Isobutyl-3-methyl-1-)butenyl-4-trifluoromethyl-2(1H)-quinolinone (Compound 651);
6-(1-Isobutyl-3-methyl)butyl-4-trifluoromethyl-2(1H)-quinolinone (Compound 652);
6-(1-Propyl)butyl-4-trifluoromethyl-2(1H)-thioquinolinone (Compound 653);
6-(3-Oxo-1-)cyclopentenyl-4-trifluoromethyl-2(1H)-quinolinone (Compound 654);
6-(3-Oxo-1-)cyclohexenyl-4-trifluoromethyl-2(1H)-quinolinone (Compound 655);
6-(3-Oxo-1-)cyclopentenyl-3-methyl-4-difluoromethyl-2(1H)-quinolinone (Compound 656);
6-(3-Oxo-1-)cyclohexenyl-3-methyl-4-difluoromethyl-2(1H)-quinolinone (Compound 657);
(xc2x1)-6-(3-Hydroxy-1-)cyclohexenyl-4-trifluoromethyl-2(1H)-quinolinone (Compound 658);
6-(1-Hydroxy-1,1-diphenyl)methyl-4-trifluoromethyl-2(1H)-quinolinone (Compound 659);
6-Diphenylmethyl-4-trifluoromethyl-2(1H)-quinolinone (Compound 660);
6-(3-hydroxy-3-methyl-1-)butynyl-4-trifluoromethyl-2(1H)-quinolinone (Compound 661);
6-(1-Hydroxy)cyclopentyl-1,4-dihydro-4,4-dimethyl-1,3-benzo[d]oxazin-2-one (Compound 662);
6-Bromo-1,4-dihydro-4,4-dimethyl-1,3-benzo[d]oxazin-2-one (Compound 663);
6-(1-Cyclopentenyl)-1,4-dihydro-4,4-dimethyl-1,3-benzo[d]oxazin-2-one (Compound 664);
6-Cyclopentyl-1,4-dihydro-4,4-dimethyl-1,3-benzo[d]oxazin-2-one (Compound 665);
6-(1-Hydroxy)cyclohexyl-1,4-dihydro-4,4-dimethyl-1,3-benzo[d]oxazin-2-one (Compound 666);
6-(1-Cyclohexenyl)-1,4-dihydro-4,4-dimethyl-1,3-benzo[d]oxazin-2-one (Compound 667);
6-Cyclohexyl-1,4-dihydro-4,4-dimethyl-1,3-benzo[d]oxazin-2-one (Compound 668);
6-(1-Hydroxy)cycloheptyl-1,4-dihydro-4,4-dimethyl-1,3-benzo[d]oxazin-2-one (Compound 669);
6-(1-Cycloheptenyl)-1,4-dihydro-4,4-dimethyl-1,3-benzo[d]oxazin-2-one (Compound 670);
6-(1-Cycloheptyl)-1,4-dihydro-4,4-dimethyl-1,3-benzo[d]oxazin-2-one (Compound 671);
6-(2,6,6-Trimethyl-1-)cyclohexenyl-1,4-dihydro-4,4-dimethyl-1,3-benzo[d]oxazin-2-one (Compound 672);
(xc2x1)-6-(3,3,5-Trimethyl-1-)cyclohexenyl-1,4-dihydro-4,4-dimethyl-1,3-benzo[d]oxazin-2-one (Compound 673);
(xc2x1)-6-(3,5,5-Trimethyl-1-)cyclohexenyl-1,4-dihydro-4,4-dimethyl-1,3-benzo[d]oxazin-2-one (Compound 674);
(xc2x1)-6-(5-Methyl-1-)cyclohexenyl-1,4-dihydro-4,4-dimethyl-1,3-benzo[d]oxazin-2-one (Compound 675);
(xc2x1)-6-(3-Methyl-1-)cyclohexenyl-1,4-dihydro-4,4-dimethyl-1,3-benzo[d]oxazin-2-one (Compound 676);
(xc2x1)-6-(2,6-Dimethyl-1-)cyclohexenyl-1,4-dihydro-4,4-dimethyl-1,3-benzo[d]oxazin-2-one (Compound 677);
(xc2x1)-6-(2-Bicyclo[2.2.1]heptenyl)-1,4-dihydro-4,4-dimethyl-1,3-benzo[d]oxazin-2-one (Compound 678);
(xc2x1)-6-(4,5-trans-Dimethyl-1-)cyclohexenyl-1,4-dihydro-4,4-dimethyl-1,3-benzo[d]oxazin-2-one (Compound 679);
(xc2x1)-6-(3,4-trans-Dimethyl-1-)cyclohexenyl-1,4-dihydro-4,4-dimethyl-1,3-benzo[d]oxazin-2-one (Compound 680);
6-(6,6-Dimethyl-1-)cyclohexenyl-1,4-dihydro-4,4-dimethyl-1,3-benzo[d]oxazin-2-one (Compound 681);
6-(5,5-Dimethyl-1-)cyclopentenyl-1,4-dihydro-4,4-dimethyl-1,3-benzo[d]oxazin-2-one (Compound 682);
(xc2x1)-6-(3,3,5-cis-Trimethyl)cyclohexyl-1,4-dihydro-4,4-dimethyl-1,3-benzo[d]oxazin-2-one (Compound 683);
(xc2x1)-6-(3,3,5-trans-Trimethyl)cyclohexyl-1,4-dihydro-4,4-dimethyl-1,3-benzo[d]oxazin-2-one (Compound 684);
(xc2x1)-6-(3-cis-Methyl)cyclohexyl-1,4-dihydro-4,4-dimethyl-1,3-benzo[d]oxazin-2-one (Compound 685);
(xc2x1)-6-(3-trans-Methyl)cyclohexyl-1,4-dihydro-4,4-dimethyl-1,3-benzo[d]oxazin-2-one (Compound 686);
(xc2x1)-6-(2,6-cis,cis-Dimethyl)cyclohexyl-1,4-dihydro-4,4-dimethyl-1,3-benzo[d]oxazin-2-one (Compound 687);
(E)-6-1,4-Dimethyl-1-)pentenyl-1,4-dihydro-4,4-dimethyl-1,3-benzo[d]oxazin-2-one (Compound 688);
6-(1-Cyclohexenyl)-1,4-dihydro-4,4-dimethyl-1,3-benzo[d]oxazin-2-thione (Compound 689);
6-(3-Oxo-1-)cyclopentenyl-1,4-dihydro-4,4-dimethyl-1,3-benzo[d]oxazin-2-one (Compound 690);
6-(3-Oxo-1-)cyclohexenyl-1,4-dihydro-4,4-dimethyl-1,3-benzo[d]oxazin-2-one (Compound 691);
(xc2x1)-6-(3-Hydroxy-1-)cyclohexenyl-1,4-dihydro-4,4-dimethyl-1,3-benzo[d]oxazin-2-one (Compound 692);
(xc2x1)-6-(3-cis-Hydroxy)cyclohexyl-1,4-dihydro-4,4-dimethyl-1,3-benzo[d]oxazin-2-one (Compound 693);
(xc2x1)-6-(3-Butyl-3-hydroxy-1-)cyclohexenyl-1,4-dihydro-4,4-dimethyl-1,3-benzo[d]oxazin-2-one (Compound 694);
6-(3-Oxo-1-)cyclohexenyl-1,4-dihydro-4,4-dimethyl-1,3-benzo[d]oxazin-2-thione (Compound 695);
6-Bromo-1,4-dihydro-4,4-dimethyl-1,3-benzo[d]oxazin-2-thione (Compound 696);
(xc2x1)-6-(3-Hydroxy-1-)cyclohexenyl-1,4-dihydro-4,4-dimethyl-1,3-benzo[d]oxazin-2-thione (Compound 697);
(xc2x1)-6-(1-Cyclohexenyl)-1,4-dihydro-4-methyl-1,3-benzo[d]oxazin-2-one (Compound 698);
(xc2x1)-6-Bromo-1,4-dihydro-4-methyl-1,3-benzo[d]oxazin-2-one (Compound 700);
6-(1-Cyclohexenyl)-1,4-dihydro-4,4,5-trimethyl-1,3-benzo[d]oxazin-2-one (Compound 701);
6-Bromo-1,4-dihydro-4,4,5-trimethyl-1,3-benzo[d]oxazin-2-one (Compound 704);
6-(1-Cyclohexenyl)-3,4-dihydro-4,4-dimethyl-2(1H)-quinolinone (Compound 705);
6-Bromo-3,4-dihydro-4,4-dimethyl-2(1H)-quinolinone (Compound 706);
6-Cyclohexyl-3,4-dihydro-4,4-dimethyl-2(1H)-quinolinone (Compound 707);
(xc2x1)-8-Bromo-6-(1-cyclohexenyl)-1,4-dihydro-4-trifluoromethyl-1,3-benzo[d]oxazin-2-one (Compound 708);
(xc2x1)-6,8-Dibromo-1,4-dihydro-4-trifluoromethyl-1,3-benzo[d]oxazin-2-one (Compound 711);
5-(3-Oxo-1-)cyclohexenyl-3,3-dimethyl-2-indolone (Compound 712);
5-Bromo-3,3-dimethyl-2-indolone (Compound 542); (xc2x1)-5-(3-Hydroxy-1-)cyclohexenyl-3,3-dimethyl-2-indolone (Compound 714);
(xc2x1)-5-(3-Oxocyclohexyl)-3,3-dimethyl-2-indolone (Compound 715);
(xc2x1)-5-(3-Oxocyclohexyl)-3,3-dimethyl-2-indolone (Compound 544); 5-Cyclohexyl-3,3-spirocyclohexyl-2-indolone (Compound 716);
5-Bromo-3,3-spirocyclohexyl-2-indolone (Compound 717);
5-Cyclopentyl-3,3-spirocyclohexyl-2-indolone (Compound 718);
6-(1-Hydroxycyclohexyl)-2(3H)-benzothiozolone (Compound 719);
6-Cyclohexenyl-2(3H)-benzothiozolone (Compound 720);
3,4-Dihydro-6-isopropyl-3-methyl-2(1H)-quinazolinone (Compound 721);
6-Bromo-3,4-dihydro-3-methyl-2(1H)-quinazolinone (Compound 722);
1-Benzyl-6-bromo-3,4-dihydro-3-methyl-2(1H)-quinazolinone (Compound 723);
1-Benzyl-6-cyclohexyl-3,4-dihydro-3-methyl-2(1H)-quinazolinone (Compound 724);
6-(2,3-Difluoro)phenyl-4-trifluoromethyl-2(1H)-quinolinone (Compound 725);
4-Trifluoromethyl-6-(3-nitro)phenyl-2(1H)-quinolinone (Compound 727);
4-Trifluoromethyl-6-(3,5-dichloro)phenyl-2(1H)-quinolinone (Compound 728);
4-Trifluoromethyl-6-(3-fluoro-5-N-hydroxyliminomethyl)phenyl-2(1H)-quinolinone (Compound 729);
4-Trifluoromethyl-6-(3-fluoro-5-formylmethylphenyl)-2(1H)-quinolinone (Compound 730);
4-Trifluoromethyl-6-(3-fluoro-5-cyano)phenyl-2(1H)-quinolinone (Compound 731);
4-Trifluoromethyl-6-(3-fluoro-5-chloro)phenyl-2(1H)-quinolinone (Compound 732);
4-Trifluoromethyl-6-(4-hydroxymethyl)phenyl-2(1H)-quinolinone (Compound 734);
4-Trifluoromethyl-6-(3-acetylphenyl)-2(1H)-quinolinone (Compound 735);
4-Trifluoromethyl-6-(4-ethylphenyl)-2(1H)-quinolinone (Compound 736);
4-Trifluoromethyl-6-(3-ethoxylphenyl)-2(1H)-quinolinone (Compound 737);
4-Trifluoromethyl-6-(3-methylphenyl)-2(1H)-quinolinone (Compound 738);
4-Trifluoromethyl-6-(3-trifluoromethylphenyl)-2(1H)-quinolinone (Compound 739);
4-Trifluoromethyl-6-(3-chlorophenyl)-2(1H)-quinolinone (Compound 740);
4-Trifluoromethyl-6-(3-fluorophenyl)-2(1H)-quinolinone (Compound 741); 4-Trifluoromethyl-6-(2-methylphenyl)-2(1H)-quinolinone (Compound 742);
4-Trifluoromethyl-6-(4-formyl)phenyl-2(1H)-quinolinone (Compound 743);
4-Trifluoromethyl-6-(4-tert-butylphenyl)-2(1H)-quinolinone (Compound 744);
4-Trifluoromethyl-6-(2-methoxyphenyl)-2(1H)-quinolinone (Compound 745);
4-Trifluoromethyl-6-(2-fluorophenyl)-2(1H)-quinolinone (Compound 746);
4-Trifluoromethyl-6-(4-acetylphenyl)-2(1H)-quinolinone (Compound 747);
4-Trifluoromethyl-6-(4-methylphenyl)-2(1H)-quinolinone (Compound 748);
4-Trifluoromethyl-6-(4-fluorophenyl)-2(1H)-quinolinone (Compound 749);
4-Trifluoromethyl-6-(4-methoxyphenyl)-2(1H)-quinolinone (Compound 750);
4-Trifluoromethyl-6-(3,5-bis-trifluoromethyl)phenyl-2(1H)-quinolinone (Compound 751);
4-Trifluoromethyl-6-(4-trifluoromethoxyphenyl)-2(1H)-quinolinone (Compound 752);
4-Trifluoromethyl-6-(2,4-dichlorophenyl)-2(1H)-quinolinone (Compound 753);
3-Fluoro-4-trifluoromethyl-6-(2-fluorophenyl)-2(1H)-quinolinone (Compound 754);
3-Fluoro-4-trifluoromethyl-6-(2,4-dichlorophenyl)-2(1H)-quinolinone (Compound 755);
4-Trifluoromethyl-6-(4-hydroxyphenyl)-2(1H)-quinolinone (Compound 756);
6-Bromo-4-methyl-2(1H)-quinolinone (Compound 757);
4-Methyl-6-(3-methoxyphenyl)-2(1H)-quinolinone (Compound 758);
4-Methyl-6-(3B-chlorophenyl)-2(1H)-quinolinone (Compound 759);
4-Methyl-6-(3-chloro-2-methylphenyl)-2(1H)-quinolinone (Compound 760);
4-Methyl-6-(2,3-dichlorophenyl)-2(1H)-quinolinone (Compound 761);
4-Methyl-6-(2,4-dichlorophenyl)-2(1H)-quinolinone (Compound 762);
4-Methyl-6-(2-methylphenyl)-2(1H)-quinolinone (Compound 763);
4-Trifluoromethyl-6-phenyl-2(1H)-quinolinone (Compound 764);
4-Trifluoromethyl-6-propio-2(1H)-quinolinone (Compound 765);
4-Trifluoromethyl-6-(1-ethylaminopropyl)-2(1H)-quinolinone (Compound 767);
4-Trifluoromethyl-6-(1-N-ethyl-N-methylaminopropyl)-2(1H)-quinolinone (Compound 768);
4-Trifluoromethyl-6-(1-hydroxy-1-methyl-2-oxopropyl)-2(1H)-quinolinone (Compound 769);
4-Trifluoromethyl-6-(4,4,4-trifluoro-1(E)-butenyl)-2(1H)-quinolinone (Compound 771);
4-Trifluoromethyl-6-(4,4,4-trifluorobutyro)-2-isopropyloxyquinoline (Compound 772);
4-Trifluoromethyl-6-(1-hydroxy-4,4,4-trifluorobutyl)-2-isopropyloxyquinoline (Compound 773);
4-Trifluoromethyl-6-(1-(3,3,3-trifluoropropyl)-1(E)-propenyl)-2(1H)-quinolinone (Compound 774);
4-Trifluoromethyl-6-(1-ethyl-1-hydroxy-4,4,4-trifluorobutyl)-2-isopropyloxyquinoline (Compound 775);
4-Trifluoromethyl-6-(1-ethyl-4,4,4-trifluoro-1(E)-butenyl)-2(1H)-quinolinone (Compound 776);
4-Trifluoromethyl-6-(1-ethyl-4,4,4-trifluoro-1(Z)-butenyl)-2(1H)-quinolinone (Compound 777);
2-Chloro-4-trifluoromethyl-6-(bis-N,N-2,2,2-trifluoroethyl)aminoquinoline (Compound 778);
2-Methoxy-4-trifluoromethyl-6-(bis-2,2,2-trifluoroethyl)aminoquinoline (Compound 779);
2-Isopropyloxy-4-trifluoromethyl-6-(bis-2,2,2-trifluoroethyl)aminoquinoline (Compound 780);
2-Ethoxy-4-trifluoromethyl-6-(bis-2,2,2-trifluoroethyl)aminoquinoline (Compound 781);
2-Acetyloxy-4-trifluoromethyl-6-(bis-2,2,2-trifluoroethyl)aminoquinoline (Compound 782);
2-(2-Dimethylamino)ethoxy-4-trifluoromethyl-6-(bis-2,2,2-trifluoroethyl)aminoquinoline (Compound 783);
2-Isobutyryloxy-4-trifluoromethyl-6-(bis-2,2,2-trifluoroethyl)aminoquinoline (Compound 784);
2-(2,2-Dimethyl)propyryloxy-4-trifluoromethyl-6-(bis-2,2,2-trifluoroethyl)aminoquinoline (Compound 785);
2-N,N-Dimethylcarbamyloxy-4-trifluoromethyl-6-(bis-2,2,2-trifluoroethyl)aminoquinoline (Compound 786);
2-Cyano-4-trifluoromethyl-6-(bis-2,2,2-trifluoroethyl)aminoquinoline (Compound 787);
4-Trifluoromethyl-6-(bis-2,2,2-trifluoroethyl)amino-2(1H)-quinolinone oxime (Compound 788);
Representative PR modulator compounds (i.e., agonists and antagonists) according to the present invention include:
6-(N-Ethyl-N-2,2-dimethylpropyl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 242);
(xc2x1)-6-(N-Propyl-N-1-methylbutyl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 251);
6-Cyclohexyl-4-trifluoromethyl-2(1H)-thioquinolinone (Compound 631);
6-(1-Cyclohexenyl)-1,4-dihydro-4,4-dimethyl-1,3-benzo[d]oxazin-2-one (Compound 667);
-6-(1-Cycloheptyl)-1,4-dihydro-4,4-dimethyl-1,3-benzo[d]oxazin-2-one (Compound 671);
6-(1-Cyclohexenyl)-1,4-dihydro-4,4-dimethyl-1,3-benzo[d]oxazin-2-thione (Compound 689);
6-(3-Oxo-1-)cyclohexenyl-1,4-dihydro-4,4-dimethyl-1,3-benzo[d]oxazin-2-thione (Compound 695);
(xc2x1)-6-(3-Hydroxy-1-)cyclohexenyl-1,4-dihydro-4,4-dimethyl-1,3-benzo[d]oxazin-2-thione (Compound 697);
6-(2,3-Difluoro)phenyl-4-trifluoromethyl-2(1H)-quinolinone (Compound 725);
4-Trifluoromethyl-6-(3-nitro)phenyl-2(1H)-quinolinone (Compound 727);
4-Trifluoromethyl-6-(3-fluoro-5-cyano)phenyl-2(1H)-quinolinone (Compound 731);
4-Trifluoromethyl-6-(3-acetylphenyl)-2(1H)-quinolinone (Compound 735).
The sequences of steps for several general schemes to synthesize the compounds of the present invention are shown below. In each of the Schemes the R groups (e.g., R1, R2, etc.) correspond to the specific substitution patterns noted in the Examples. However, it will be understood by those skilled in the art that other functionalities disclosed herein at the indicated positions of compounds of formulas I through XXXIII also comprise potential substituents for the analogous positions on the structures within the Schemes.

The above reaction-sequence shows the general formulation of quinolinone compounds which are modulators of androgen and progesterone receptors. In the above reaction sequence, an aniline compound is converted to a quinolinone compound by a Knorr cyclization with an alpha-keto ester compound. The quinolinone may then be converted to various derivatives including but not limited to thioquinolinones, quinolines, alkylated quinolinones, and functionalized quinolinones. In the above scheme, R represents various aromatic substituents contained on the aniline compound known to those skilled in the art. The R group on the quinolinone compounds may be interconverted to various substituents including but not limited to nitro, amino, alkylamino, halogen, alkyl, aryl, dialkylamino, pyrrole, and oxazolidene groups by various chemical reactions known to those skilled in the art. The Rxe2x80x2 group represents various aromatic subsitutents known to those skilled in the art and may originate from any of the 3, 5, and 6 positions on the ring, and n may be from 0 to 3. The Rxe2x80x2 groups on the quinolinone compounds may also be interconverted to various substitutents by chemistry known to those skilled in the art to form derivative quinolinone compounds. Schemes I through VI below show various preferred embodiments of the current invention. 
Scheme I describes a method to prepare quinolinone compounds such as Structure 5, nitro-quinolinone compounds such as Structure 6, and amino-2-quinolinone compounds such as Structure 3 through modified Knorr reactions. Thermal condensation of a 4-aminoacetanilide (Structure 1) with a 3-ketoester, for example, ethyl 4,4,4-trifluoroacetoacetate in nitrobenzene affords a bis-amide such as Structure 2. When a bis-amide compound of Structure 2 is treated with concentrated sulfuric acid at 60-100xc2x0 C., aminoquinolinone compounds of Structure 3 are produced. An alternate process of preparing 6-aminoquinolinone compounds such as Structure 3 starts with a similar Knorr reaction. The synthesis begins with reaction of an aniline such as Structure 4 and a 3-ketoester in refluxing toluene followed by treatment of a Lewis acid such as p-toluenesulfonic acid to produce a 2-quinolinone such as Structure 5. Classic nitration of the 2-quinolinone (e.g., Structure 5) selectively provides a 6-nitroquinolinone compound (e.g., Structure 6). Reduction of the nitroquinolinone such as Structure 6 under standard reduction conditions (e.g., metal catalyzed hydrogenation or tin chloride reduction) affords aminoquinolinone compounds such as Structure 3. 
Scheme II describes the N-substitution of the 6-amino-2-quinolinone such as Structure 3 and the conversion of Structure 3 to mercapto analogues. A two-step sequential reductive alkylation of the aminoquinolinone (e.g., Structure 3) with an aldehyde or ketone or acid in the presence of a reducing agent, such as sodium cyanoborohydride or sodium borohydride affords compounds of Structure 7. Treatment of an amino-2-quinolinone compound (e.g., Structure 3) with an acylating agent, such as acetyl chloride or anhydride, in the presence of a base such as pyridine or triethylamine provides amides or sulfonamides compounds as shown in Structure 7. Treatment of quinolinones of Structure 7 with Lawesson""s reagent provides a corresponding thioquinolinone compound of Structure 8. Treatment of compounds of Structure 7 with an alkylating agent such as alkyl iodide in the presence of sodium hydride in a polar solvent, such as tetrahydrofuran gives compounds of Structure 9. Direct alkylation of Structure 3 provides compounds of Structure 10. The mercapto analogues of Structures 12 and 13 are prepared through diazo intermediate of Structure 11. 
Scheme III describes an alternate method for the syntheses of 6-amino compounds of Structures 7, 20, 21 and 22. The process begins with a step-wise Knorr reaction, in which 4-Bromoaniline (Structure 14) and a 3-ketoester such as the trifluoroacetoacetate are heated in reflux in toluene provides an amide such as Structure 15 and heating in concentrated sulfuric acid affords 4-bromoquinolinone such as Structure 16. Treatment of quinolinones such as Structure 16 with 2-iodopropane, catalyzed by cesium fluoride in DMF afford alkoxyquinoline compounds such as Structure 17. Palladium-catalyzed coupling reaction between bromoquinolines such as Structure 17 and alkylamines gives compounds of Structures 18 and 19. Hydrolysis of the quinoline compounds (Structures 18 and 19) in acidic condition provide compounds of Structures 7 and 20. Compounds of Structures 21 and 22 are prepared in a similar fashion. 
Scheme IV shows additional alkylation strategies of 6-aminoquinolinone of Structure 3 to provide 6-oxazolidine-quinolinone compounds (e.g., Structure 25), 6-cycloalkylamino-quinolinone compounds (e.g., Structure 20) and compounds of Structures 7 and 27.
The process of Scheme IV begins with reductive alkylation of an aminoquinolinone (e.g., Structure 3), with xcex1-hydroxyketones of Structure 23 in the presence of a reducing agent such as sodium cyanoborohydride to provide compounds of Structure 24. Formation of an oxazolidine compound such as Structure 25 is carried out by treatment of an aminol compound such as Structure 24 with an aldehyde or its corresponding hydrate in the presence of an acid. Quinolinone compounds of Structure 20 are prepared by condensation of an aminoquinolinone (e.g., Structure 3) and a diketone such as Structure 23 in the presence of a reducing agent. Compounds such as Structure 7 are prepared by alkylation of quinoline intermediate of Structure 26 derived from Structure 3 with an alkyl halide. Direct alkylation of Structure 3 with halides affords mixture compounds of Structures 7 and 27. 
Scheme V shows the preparation of substituted quinolinones of Structures 20a and 31 from anilines of Structure 28 or 6-aminoquinolinones such as Structure 3. The process begins with a Knorr cyclization of a meta- or ortho-substituted aniline (e.g., Structure 28) with a 3-ketoester to afford compounds of Structure 29. Nitration of compounds such as Structure 29 followed by reduction of the nitro group affords predominantly 6-amino compounds of Structure 30. Alternately compounds of Structure 30 are also obtained by modification of 6-aminoquinolinones such as Structure 3. For example, bromination of compounds of Structure-3 with NBS provides a 7-bromo-2-quinolinone compound (e.g., Structure 30, where R3=bromo). Quinolinone compounds as shown in Structures 20a and 31 are synthesized in a similar fashion as that described in Schemes II and IV from the substituted 6-amino-2-quinolinones of Structure 30. 
Scheme VI describes the side-chain modification of the 6-cycloamino-2-quinolinones of Structure 32. The process of Scheme VI starts with the reduction of an ester derivative of Structure 32 to give hydroxycompounds of Structure 33. Conversion of compounds of Structure 33 to tosylated analogues followed by nucleophilic substitution affords compounds of Structure 34. Oxidation of compounds of Structure 33 provides the formyl derivatives of Structure 35. Addition of a nucleophile to compounds of Structure 35 gives secondary alcohol analogues of Structure 36. Further manipulation affords compounds of Structure 37. 
Scheme VII describes Knorr reactions of substituted anilines to produce functionalized quinolinone compounds. The process of Scheme VII starts with alkylation of an aniline compound such as Structure 38 with trifluoroacetaldehyde in the presence of sodium cyanoborohydride followed by zinc reduction to provide an alkylated bis-amine compound such as Structure 39. A typical Knorr procedure converts the alkylated amine compound 39 and ethyl 4,4,4-trifluoroacetoacetate to a quinolinone compound such as 40. Reductive alkylation of compounds of 40 provides a bis-alkylaminoquinolinone such as Structure 41. Treatment of compounds of Structure 41 with thiophenol affords 7-hydroxyquinolinone compounds such as 42. 
Scheme VIII describes the synthesis of 6-alkylaminocoumarins, as demonstrated by Structure 45, from phenol through a similar route as that described in Schemes I and II. A mixture of a phenol compound and a 3-ketoester such as ethyl 4,4,4-trifluoroacetoacetate are heated in refluxing toluene in the presence of TsOH to afford a coumarin compound e.g., Structure 43. Nitration of coumarin compounds (e.g., Structure 43) followed by hydrogenation give aminocoumarin compounds such as Structure 44. Sequential reductive alkylation provides dialkylamino-coumarin compounds as shown in Structure 45. Hydrogenation of a dialkylamino-coumarin compound (e.g., Structure 45) affords compounds Structure 46. 
In another preferred embodiment, the syntheses of benzo-oxazinone compounds (e.g., Structure 49) and derivatives thereof (e.g., Structures 51 and 52) are shown in Scheme IX.
The process of Scheme IX begins with the treatment of an alkenylaniline compound such as Structure 47 with chloroformate in the presence of DMAP in THF to produce carbamates such as Structure 48. Benzoxazinone compounds such as Structure 49 (Wxe2x95x90O) are produced by p-tolylsulfonic acid catalyzed intra-molecular cyclization of a carbamate (e.g., Structure 48).
An alternate synthesis of benzo-oxazinone compounds of Structure 49 is also shown in Scheme IX. In this synthetic route, carbon nucleophiles are added to 2-aminobenzoic acid to give the amino-alcohol compound 50, which is converted to an aminobenzo-oxazinone compound such as Structure 49 by either 1,1xe2x80x2-carbonyldiimidazole in THF or the carbonate-cyclization route as described above. A classic nitration reaction of the aromatic benzoxazinone compound by nitric acid in concentrate sulfuric acid followed by palladium catalyzed hydrogenation produces amino compounds such as Structure 51. A two-step sequential reductive alkylation as described previously produces dialkylamine-benzoxazinone compounds as shown in Structure 52. 
In another preferred embodiment, bioisosteres of 6-amino-2-quinolinones such as 5-amino-oxinole, 6-amino-benzoxazinone and quinoline compounds, which are useful AR and PR modulators, are prepared from a corresponding bicyclic compound. The bicyclic compounds such as Structures 53, 56 and 58 are prepared by synthetic methods known to those skilled in the art.
Scheme X describes a synthetic process for preparing 5-bisalkylamino-oxindole compounds such as Structure 55 and 6-bisalkylated compounds of Structures 57 and 59. The method for preparing these compounds is described in Scheme IX and is analogous to the preparation of compounds such as Structure 52 from the corresponding quinolinone compound. The process involves sequential nitration, reduction and/or alkylation of the amine to produce compounds of Structures 55, 57 and 59. 
Scheme XI describes a preferred synthetic method to prepare 7-alkylamino-2-quinolinones such as Structure 63 via the Knorr reaction as previously described. The process of Scheme XI begins with a modified Knorr cyclization of 1,3-phenylenediamines of Structure 60 to give a 7-aminoquinolinone compound such as Structure 61. A sequential reductive alkylation of Structure 61 in a similar process as that described in Scheme II affords compounds such as Structure 62. Alkylation of quinolinone such as 62 with alkyl iodide in the presence of sodium hydride generates 1-alkyl quinolinone compounds such as Structure 63. 
In another preferred aspect of the invention, alkylamino-quinolinone compounds (e.g., Structure 66) are prepared from a corresponding amino-quinolinone compound. Schemes XII, XIII and XIV describe the methods of introducing a quaternary carbon next to the amino position.
The process of Scheme XII begins with the treatment of a 7-aminoquinolinone such as Structure 61a with acetic acid in acetone to afford an alkyl amino-quinolinone compound such as Structure 64. Methyllithium addition to a compound such as Structure 64 in THF provides the corresponding alcohol adduct e.g., Structure 65. An acid catalyzed dehydration of an amino alcohol compound such as 65 gives an alkene amino-quinolinone compound such as 66. 
In another preferred reaction sequence, alkyl-quinolinones are produced by a Knorr cyclization of a diamine compound as previously described. Subsequent alkylation and oxidation produces alkyl-quinolinone compounds. The alkylamine-quinolinones may then be further converted to various derivative compounds by reactions known to those skilled in the art as exemplified in the examples below.
Scheme XIII describes an alternate procedure to synthesize 2-quinolinones with a quaternary carbon adjacent to the 7-nitrogen. The process of Scheme XIII begins with a typical Knorr cyclization of a 1,3-phenylenediamine with a xcex1-ketoester, ethyl 4,4,4-trifluoroacetoacetate, to afford an aminoquinoline compound such as 67 as a minor product. Alkylation of an aminoquinoline compound such as 67 with an amide such as N-phenyl-xcex1-bromoisobutyramide in the presence of sodium hydride affords an alkylated quinoline product such as 68 in good yield. Hydrolysis of an alkylated quinoline compound (e.g., Structure 68) with HI provides a 2-quinolinone such as 69. Methylation of an alkylated quinoline compound such as 68 with iodomethane in the presence of sodium hydride followed by HI mediated hydrolysis produces a quinolinone such as Structure 70. Reduction of an amide compound such as 70 with DIBAL-H affords an aldehyde compound such as 71 and an alcohol product such as 72. Wittig reaction of aldehydes such as 71 affords olefins such as Structure 73. Hydrogenation of an allylamino-quinolinone compound such as Structure 73 produces a corresponding alkylamino-quinolinone compound as shown in Structure 74. 
In another preferred aspect of the invention, alkylamino-quinolinone compounds are produced by copper chloride catalyzed substitution of an amino-quinolinone compound. Scheme XIV describes an alternate N-alkylation method for the preparation of alkylamino-quinolinone compounds. Treatment of an amino quinolinone compound such as 61a and propargyl acetate with copper chloride and a base such as triethylamine in THF affords alkylamine-quinolinone products such as 75. Hydrogenation of an amino-acetylene compound such as 75 provides an alkylamino quinolinone compound as shown in Structure 76 in excellent yield. 
Alkyl-diamino compounds (e.g. Structure 78) are produced by two alternate synthetic methods in another preferred synthetic route as shown in Scheme XV. Alkylations of amino compounds as shown below are reactions known to those skilled in the art. The reaction as shown below is as an example of the preparation of these types of compounds.
The process of Scheme XV begins with alkylation of a mono-protected 1,3-phenylenediamine followed by trifluoroacetic acid (TFA) mediated de-protection to produce diamino compounds such as Structure 78. Alternately, alkylation of a 3-nitroaniline followed by a reduction of the nitro group generates the same intermediates of Structure 78. Knorr cyclization as previously described in the presence of a xcex1-keto-ester such as ethyl 4,4,4-trifluoroacetoacetate affords compounds such as Structure 79 in good yield. 
Substituted diamino compounds are produced in another preferred embodiment of the invention. The diamino compounds are then further reacted to produce quinolinone compounds via the Knorr reaction as previously described. Scheme XVI describes a synthetic process for producing alkoxy-alkylamino-quinolinone compounds such as Structure 84.
The process starts with substitution of a bis-nitrofluorobenzene with 2,2,2-trifluoroethyanol in the presence of a base, such as sodium hydride to provide an alkoxy-nitrobenzene compound such as Structure 81. Conversion of bis-nitro groups to bis-amino groups is accomplished by hydrogenation or metal reduction to give aniline compounds such as Structure 82. A standard Knorr reaction with ethyl 4,4,4-trifluoroacetoacetate and p-tolylsufonic acid affords alkoxy-quinolinones such as Structure 83 in high yield. An alkoxy-amino-quinolinone compound such as 83 may subsequently be alkylated as previously described. For example, reductive alkylation of a compound such as Structure 83 with an aldehyde and sodium cyanoborohydride gives alkoxy-alkylamino-quinolinone compounds as shown in Structure 84. 
In another preferred reaction, substituted diamine compounds (e.g., Structure 87) are produced by electrophilic aromatic substitution of activated aromatic amino-benzene rings. The substituted diamine compounds are then further reacted to produce quinolinone compounds (e.g., Structure 88) and subsequent quinolinone derivatives thereof (e.g., Structure 89) as previously described. Quinolinone compounds as shown in Scheme XVII are useful PR and AR modulators as described herein.
Scheme XVII describes processes to synthesize substituted alkylaminoquinolinone compounds such as 89. Treatment of ortho-substituted aniline such as Structure 85 or a 4-substituted aniline such as 90 with nitric acid in concentrated sulfuric acid generates meta-nitrated products such as 86 or 91 in high yield. Hydrogenation of the nitro group on compounds such as 86 or 91 provides the Knorr precursors as shown as Structure 87. Treatment of 1,3-phenylenediamines such as 87 with ethyl 4,4,4-trifluoroacetoacetate in refluxing toluene in the presence of a catalytic amount of acid, such as p-tolylsufonic acid, affords quinolinone compounds as shown in Structure 88. Additional alkylation at the 7-amino group provides more functionalized compounds such as Structure 89 as previously described. 
In a preferred aspect of the invention, functionalized quinolinones or functionalized dihydro-quinolinones are prepared from the corresponding substituted diamino-benzene compound (e.g. Structure 92). The amino portion of the quinolinone and dihydro-quinolinone compounds (e.g. Structures 94 and 93), may then be converted to other functional groups by chemical reactions known to those skilled in the art. Examples of such conversions are demonstrated in Scheme XVIII, for example in the preparation of compounds such as 95, 96, 97 and 100.
Scheme XVIII above describes methods of preparing functionalized quinolinones. The process of Scheme XVIII begins with modified Knorr reactions of diamine 92 with ethyl 4,4,4-trifluoroacetoacetate. In the p-tolylsufonic acid catalyzed refluxing toluene condition quinolinone compounds such as 94 are major products. In an alternate synthesis, the reaction is carried out in refluxing ethanol, which produces compounds such as Structure 93 as major products. Compounds such as 93 may then be converted to quinolinones such as 94 by acid catalyzed dehydration. The 5-amino group of compounds 93 or 94 is converted to 5-hydroxy derivatives of Structure 95 by diazotization-hydrolysis conditions using sodium nitrite and sulfuric acid. A similar condition by sodium nitrite and chloride converts the 5-amino to 5-chloro derivatives of Structure 98. Reductive alkylation of compounds of Structures 94 and 99 affords compounds of Structures 96 and 100. 
Another synthetic route into functionalized quinolinone compounds (e.g. Structures 102 and 104) is shown in Scheme XIX. Scheme XIX describes the synthesis of substituted quinolinone compounds such as Structures 102 and 104 under similar Knorr reaction conditions as that described in Scheme 1. The Knorr reaction may also be used on substituted aniline compounds (e.g. Structure 101) to produce functionalized quinolinone compounds such as Structure 102. The functionalized quinolinone compounds as shown above may then be converted to other functional groups to produce additional quinolinone derivatives such as compounds of Structure 104 as described herein.

In another aspect of the invention, halogenated quinolinones, benzo-oxazinones, indolones, benzothiozolones, and quinazolinones (i.e., arylhalogen compounds) produce alkylated derivatives by a Cxe2x80x94C coupling of the arylhalogen carbon and a ketone with a lithium reagent. The above reaction sequence depicts the conversion of arylhalogen compounds to arylalkyl compounds by reaction of the aryl halide compound with a ketone. Schemes XX through XXIX depict further examples of this type of functional group conversion and are provided to further illustrate the reaction with various ketones and aryl compounds. 
In another aspect of the invention, functionalized quinolinone compounds (e.g., Structure 105 and 109) are produced by a Cxe2x80x94C coupling of a halo-quinolinone such as Structure 16a and a ketone as shown in Schemes XX and XXI. The halo-quinolinone may be produced by either of two synthetic routes as shown below in Scheme XX. Scheme XX describes the synthesis of a number of functionalized quinolinone compounds.
3-Fluorinated-quinolinone compounds such as Structure 16a may be formed by treatment of a 3-ketoamide 15 with a fluorination reagent, such as fluorobenzenesulfonimide, to provide a fluorinated derivative product such as Structure 15a, which is converted to the 3-fluoro quinolinone compound 16a (R=fluorine) by the Knorr cyclization with concentrated sulfuric acid.
A 7-methoxy analogue of Structure 16a is prepared by NBS bromination of quinolinone 29a. Addition of a dianion generated from a bromo-quinolinone such as 16a by two equivalents of base, such as alkyllithium, to a ketone affords the tertiary alcohols as shown in Structure 105. Dehydration of an alcohol such as 105 with a catalytic amount of acid, such as sulfuric acid, gives olefins of Structure 106. Subsequent hydrogenation of olefins such as 106 provides an alkyl-quinolinone such as Structure 107. A thioquinolinone derivative may be synthesized by treatment of compounds 107 with Lawesson""s reagent in toluene as previously described. 
Scheme XXI describes a process of preparing alkenyl-quinolinone compounds. Addition of the dianion generated from a bromoquinolinone such as 16b by methyllithium and n-butyllithium to a protected cyclic 1,3-diketone affords oxo-alkenyl-quinolinone compounds such as Structure 109 upon acid mediated hydrolysis of the adducts. Reduction of the oxo group on a compound such as 109 with DIBAH provides the alcohol derivative as shown in Structure 110.
A further example of the conversion of arylhalogen compounds (e.g. Structure 16) to arylalkyl compounds is shown in Scheme XXII. Scheme XXII describes the preparation of additional 6-alkyl 2-quinolinone compounds from the quinolinone dianion in a preferred aspect of the invention. Addition of a dianion generated from a bromo quinolinone, methyllithium and n-butyllithium to benzophenone gives an alkyl quinolinone such as compound 111. Reduction of compound 111 with triethylsilane in the presence of an acid catalyst, such as TFA, affords an alkyl-quinolinone compound such as 112.
In a further embodiment of the invention, aryl halogen compounds are converted to aryl alkynes by a palladium catalyzed coupling reaction between the aryl halogen (e.g., Structure 16) and a terminal alkyne as shown above in Scheme XXII. For example, a palladium(II) catalyzed reaction of a bromoquinolinone such as 16 and a terminal alkyne such as dimethyl propargyl alcohol provides an alkynyl-quinolinone compound such as 113.
A method of converting arylhalides to arylalkyl compounds is also employed with benzo-oxazinone compounds as shown in the above example. Scheme XXIII describes methods of synthesizing alkyl 1,3-benzo[d]oxazin-2-one compounds.
The process of Scheme XXIII begins with a bromination of a compound such as 49a with bromine to give a bromobenzo-oxazinone compound such as 114. Addition of the dianion generated from the lithiation of a compound such as 49a to a ketone provides the hydroxy-alkyl adducts of Structure 115. Dehydration of alcohol derivative 115 with a catalytic amount of sulfuric acid affords compounds such as Structure 116, which may be hydrogenated to give compounds such as Structure 118. Benzothiooxazinone compounds as shown in Structure 117 are prepared from the corresponding carbonyl compound (e.g., such as Structure 116) by treatment with Lawesson""s reagent as previously described. 
Scheme XXIV describes additional methods to prepare alkyl benzo-oxazinones. The process of Scheme XXIV begins with addition of the dianion generated from lithiation of compound 114 by alkyllithium to a protected 1,3-cyclodiketone. Hydrolysis of adducts with an acid affords alkene compounds Structure 119. Addition of n-butyllithium to an enone such as 119 provides a tertiary alcohol such as 122. Reduction of the enone 119 with DIBAL-H gives a secondary alcohol such as 120. Hydrogenation affords compound such as 121. Alkyl thio-benzo-oxazinone compounds are prepared by a similar process but using a thiobenzo-oxazinone 10 such as 118a in place of the oxo compound. 
In another preferred aspect of the invention, substituted benzo-oxazinone compounds (e.g., Structure 125) are prepared for an amino-benzoic acid and an organometallic reagent to form a hydroxy-aniline compound (e.g., Structure 124) with either a halide or carbonyl diimidazole to form a benzo-oxazinone. The process of Scheme XXV begins with addition of either alkyl lithium or a Grignard reagent to a 2-aminobenzoic acid such as Structure 123 to generate amino alcohol compound such as Structure 124. A previously described cyclization procedure from either 1,1xe2x80x2-carbonyldiimidazole treatment or acid catalyzed carbamate intermediate affords compounds such as Structure 125. Treatment of benzo-oxazinone compounds (e.g., Structure 125) with bromine provides brominated benzo-oxazinone compounds such as Structure 126. Addition of an anion generated from compounds such as 126 and an alkyl lithium reagent to a ketone such as cyclohexanone affords compounds such as Structure 127. The alkenyl-benzo-oxazinone compound (e.g., 127) may be hydrogenated to give alkyl compounds such as Structure 128.
Scheme XXVI describes a process to introduce a trifluoromethyl group at the 4-position of benzo-oxazinone compounds. The process starts with addition of an N-protected 2-aminoaryl lithium generated by metal halogen exchange of 2-aminobromobenzene and n-butyllithium to ethyl trifluoroacetate followed by a reduction with sodium borohydride to provide compounds such as 129. Acid catalyzed cyclization of compounds such as 129 afford benzo-oxazinone compounds such as 130. The benzo-oxazinone compound may subsequently be treated with bromine to generate a bis-brominated product such as 131. As previously described, the bromine may be substituted with an alkyl group. For example, the 6-cyclohexenyl derivative 132 is prepared in a similar fashion as that described in Scheme XXV. 
Scheme XXVII describes methods to prepare alkyl oxindole derivatives by bromination of the oxindole followed by substitution of the bromine group with an alkyl group as previously described. The process starts with alkylation of 2-indolone with alkyl halides in the presence of n-butyllithium followed by selective bromination to afford brominated oxindole compounds (e.g., Structure 133). The alkyl-indolone compounds are prepared from a bromo compound such as 133 by a procedure similar to that as described in Scheme XXV. 
Scheme XXVIII describes a synthetic route of producing alkyl-benzothiozolones. The process is similar to that as described in Scheme XXV but using a halogenated benzothiozolone compound. 
Scheme XXIX describes a process to prepare 2-quinazolinones. The process of Scheme XXIX begins with bromination of compound 140 to afford compound 141, which is derivatized by treatment with benzyl bromide in the presence of sodium hydride to give compound 142. A palladium catalyzed aromatic substitution of compounds of Structure 141 or 142 by Grignard reagents provides compounds of Structure 143. 
Scheme XXX describes an alternate method of preparing aryl-quinolinones by a modified Suzuki coupling reaction. The process starts with palladium catalyzed biaryl coupling of a bromo compound such as Structure 16c, a brominated quinolinone, with an aryl boronic acid (e.g., Structure 144). Aryl compounds such as Structure 145 are produced in this manner. The boronic acids of Structure 144 come from commercial sources or may be generated from aryl bromides by a standard three-step procedure which includes metal halogen exchange, addition to methyl borate and acidic work-up. Aryl substituted compounds of the present invention (e.g., Structure 145) may be further functionalized by modification of the substituents on the aryl group by standard synthetic methods known to those skilled in the art. Alternately, aryl substituted compounds of the present invention such as Structure 145 may be prepared from the aryl aniline (e.g., 6-arylaniline, Structure 147) as shown above by a Knorr reaction procedure as previously described. 
Scheme XXXI describes additional methods to prepare 6-substituted 2-quinolinones such as Structures 149, 150, 152 and 153. Lithiation of Structure 17 followed by addition to a Weinreb""s amide afford compounds of Structure 148. Hydrolysis of quinolines such as Structure 148 provides compounds of Structure 149. Compounds of Structure 150 are obtained by reductive amination of compounds such as Structure 149. Addition of a nucleophile to quinoline ketones of Structure 148 generates alcohols of Structure 151, which are treated with acid to afford compounds of Structures 152 and 153. 
Scheme XXXII describes the conversion of 2-quinolinones of Structure 7 to 2-substituted quinoline such as Structures 154, 155 and 156 by the chemical transformations known to those skilled in the art. 
Scheme XXXIII describes methods to prepare compounds with a diazo containing side chain. Treatment of 6-aminoquinolinones such as Structure 7a with NaNO2 affords compounds of Structure 157. Reduction of nitroso compounds such as Structure 157 followed by alkylation provide analogues of Structure 158. Alkylation or acylation of hydrazine such as Structure 159 generates compounds of Structures 160 and 161.
The compounds of the present invention also include racemates, stereoisomers and mixtures of said compounds, including isotopically labeled and radio-labeled compounds. Such isomers can be isolated by standard resolution techniques, including fractional crystallization and chiral column chromatography.
As noted above, any of the steroid modulator compounds of the present invention can be combined in a mixture with a pharmaceutically acceptable carrier to provide pharmaceutical compositions useful for treating the biological conditions or disorders noted herein in mammalian, and more preferably, in human patients. The particular carrier employed in these pharmaceutical compositions may take a wide variety of forms depending upon the type of administration desired, e.g., intravenous, oral, topical, suppository or parenteral.
In preparing the compositions in oral liquid dosage forms (e.g., suspensions, elixirs and solutions), typical pharmaceutical media, such as water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like can be employed. Similarly, when preparing oral solid dosage forms (e.g., powders, tablets and capsules), carriers such as starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like will be employed. Due to their ease of administration, tablets and capsules represent the most advantageous oral dosage form for the pharmaceutical compositions of the present invention.
For parenteral administration, the carrier will typically comprise sterile water, although other ingredients that aid in solubility or serve as preservatives, may also be included. Furthermore, injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents and the like will be employed.
For topical administration, the compounds of the present invention may be formulated using bland, moisturizing bases, such as ointments or creams. Examples of suitable ointment bases are petrolatum, petrolatum plus volatile silicones, lanolin, and water in oil emulsions such as Eucerin(trademark) (Beiersdorf). Examples of suitable cream bases are Nivea(trademark) Cream (Beiersdorf), cold cream (USP), Purpose Cream(trademark) (Johnson and Johnson), hydrophilic ointment (USP), and Lubriderm(trademark) (Warner-Lambert).
The pharmaceutical compositions and compounds of the present invention will generally be administered in the form of a dosage unit (e.g., tablet, capsule etc.) at from about 1 xcexcg/kg of body weight to about 500 mg/kg of body weight, more preferably from about 10 xcexcg/kg to about 100 mg/kg, and most preferably from about 20 xcexcg/kg to about 20 mg/kg. As recognized by those skilled in the art, the particular quantity of pharmaceutical composition according to the present invention administered to a patient will depend upon a number of factors, including, without limitation, the biological activity desired, the condition of the patient, and tolerance for the drug.
The compounds of this invention also have utility when radio- or isotopically-labeled as ligands for use in assays to determine the presence of AR or PR in a cell background or extract. They are particularly useful due to their ability to selectively activate androgen receptors or progesterone receptors, and can therefore be used to determine the presence of such receptors in the presence of other steroid receptors or related intracellular receptors.
Due to the selective specificity of the compounds of this invention for steroid receptors, these compounds can be used to purify samples of steroid receptors in vitro. Such purification can be carried out by mixing samples containing steroid receptors with one or more of the compounds of the present invention so that the compounds bind to the receptors of choice, and then separating out the bound ligand/receptor combination by separation techniques which are known to those of skill in the art. These techniques include column separation, filtration, centrifugation, tagging and physical separation, and antibody complexing, among others.
The compounds and pharmaceutical compositions of the present invention can advantageously be used in the treatment of the diseases and conditions described herein. In this regard, the compounds and compositions of the present invention will prove particularly useful as modulators of male sex steroid-dependent diseases and conditions such as the treatment of acne, male-pattern baldness, male hormone replacement therapy, wasting diseases, hirsutism, stimulation of hematopoiesis, hypogonadism, prostatic hyperplasia, osteoporosis (agonist), male contraception (agonist), impotence (agonist), cancer cachexia (agonist) various hormone-dependent cancers, including, without limitation, prostate and breast cancer and as anabolic agents.
The compounds and pharmaceutical compositions of the present invention possess a number of advantages over previously identified steroidal and non-steroidal compounds.
Furthermore, the compounds and pharmaceutical compositions of the present invention possess a number of advantages over previously identified steroid modulator compounds. For example, the compounds are extremely potent activators of AR, preferably displaying 50% maximal activation of AR at a concentration of less than 100 nM, more preferably at a concentration of less than 50 nM, more preferably yet at a concentration of less than 20 nM, and most preferably at a concentration of 10 mM or less. Also, the selective compounds of the present invention generally do not display undesired cross-reactivity with other steroid receptors, as is seen with the compound mifepristone (RU486; Roussel Uclaf), a known PR antagonist that displays an undesirable cross reactivity on GR and AR, thereby limiting its use in long-term, chronic administration. In addition, the compounds of the present invention, as small organic molecules, are easier to synthesize, provide greater stability and can be more easily administered in oral dosage forms than other known steroidal compounds.